Strategic Plan 

Fiscal Years 2020-2024 

Turning Discovery Into Health 
 

 

 

 

 

 

 

 

 

 

TABLE OF CONTENTS 

DIRECTOR’S MESSAGE..................................................................................................................... 4 

EXECUTIVE SUMMARY .................................................................................................................... 7 

INTRODUCTION, MISSION, AND STRUCTURE .....................................................................12 

Introduction ............................................................................................................................... 12 

Mission and Statutory Authority............................................................................................... 14 

NIAMS Organizational Structure ............................................................................................. 14 

CROSS-CUTTING SCIENTIFIC THEMES ..................................................................................16 

Precision Medicine for Arthritis and Musculoskeletal and Skin Diseases ............................... 17 

Shared Mechanisms in Health and Among Diseases................................................................ 19 

Patient-Centric Approaches to Health and Disease .................................................................. 21 

Health and Disease in Diverse Populations .............................................................................. 23 

DISEASE- AND TISSUE-SPECIFIC SCIENTIFIC OBJECTIVES ........................................26 

Advancing and Accelerating Systemic Rheumatic and Autoimmune Diseases Research ....... 27 

Advancing and Accelerating Skin Biology and Diseases Research ......................................... 45 

Advancing and Accelerating Bone Biology and Diseases Research ........................................ 65 

Advancing and Accelerating Muscle Biology and Diseases Research..................................... 85 

Advancing and Accelerating Joint Biology, Diseases, and Orthopaedics Research ................ 99 

MANAGEMENT, SCIENTIFIC STEWARDSHIP, AND ACCOUNTABILITY................121 

Priority Setting........................................................................................................................ 122 

Workforce Recruitment, Development, Retention, and Diversity.......................................... 124 

Innovation ............................................................................................................................... 127 

Research Partnerships ............................................................................................................. 128 

Inclusion of Diverse Populations as Participants in Biomedical Research............................. 131 

Performance Measures and Assessment ................................................................................. 132 

Information Dissemination and Outreach............................................................................... 133 

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APPENDICES.......................................................................................................................................137 

Appendix 1: Overview of the Development Process.............................................................. 137 

Appendix 2: Requests for Information Published in the NIH Guide for 

Grants and Contracts............................................................................................................... 139 

Appendix 3: Development Timeline for the NIAMS Strategic Plan for 

Fiscal Years 2020-2024 .......................................................................................................... 144 

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DIRECTOR’S MESSAGE 

Promoting the Unexpected 

The National Institute of Arthritis and Musculoskeletal 

and Skin Diseases (NIAMS) is pleased to present its 

Fiscal Years 2020-2024 Strategic Plan. The fields that 

NIAMS supports have seen major advances in recent 

years and are now poised for additional rapid progress. 

Therefore, the NIAMS Strategic Plan conveys both the 

tremendous potential of the current research trajectory 

and the Institute’s aspirational vision for how work over 

the next 5 years may lead to meaningful improvements 

in human health. 

Mission 

The NIAMS mission is to support 

research into the causes, 

treatment, and prevention of 

arthritis and musculoskeletal and 

skin diseases; training of basic and 

clinical scientists to carry out this 

research; and dissemination of 

information on research progress 

in these diseases. 

Importantly, this plan is not intended to be a rigid 

roadmap for investigators to follow. While we will 

continue to invest in various well-defined areas, we will also seek to foster a rich and adaptable 

research environment that enables scientists to capitalize on opportunities as they arise. By 

putting structures in place to identify, promote, and support advances that we cannot predict at 

the present, we hope to stimulate new areas that are unexpected and transformative. Thus, this 

Plan for the next 5 years should be viewed not as directions to a defined destination, but rather as 

a point of departure for exploration to spark unanticipated discoveries. 

Goal 

The goal of the plan is to advance 

and accelerate research into the 

causes, treatment, and prevention 

of arthritis and musculoskeletal 

and skin diseases. The ultimate 

goal of these efforts is to develop 

patient-centered, personalized 

ways to improve outcomes and 

thereby “turn discovery into 

health.” 

This strategy of promoting the unexpected has 

important implications for priority setting. First, 

NIAMS must look to the research community for new 

ideas, rather than prescribing what gets done. Second, it 

requires maintenance of a broad base of researchers. 

Third, funding must be based on new and promising 

ideas and not just on past performance. Therefore, we 

will continue to value and support the best ideas 

proposed in investigator-initiated research project 

grants. Simultaneously, NIAMS must be poised to 

embrace unexpected opportunities for collaborations 

with other NIH components, advocacy organizations, 

and industry to fund larger scale, team science 

approaches, such as the Osteoarthritis Initiative, the 

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Accelerating Medicines Partnership, the Molecular Transducers of Physical Activity 

Consortium, and the NIH Back Pain Consortium Research Program. 

To support this strategy, the Strategic Plan describes potential research areas of interest over the 

next 5 years. Although it is not possible to reference every disease or condition within our broad 

portfolio, it covers the following five research objectives related to the core tissue- and diseasespecific areas within the NIAMS mission, namely, advancing and accelerating: 

• Systemic rheumatic and autoimmune diseases research; 

• Skin biology and diseases research; 

• Bone biology and diseases research; 

• Muscle biology and diseases research; and 

• Joint biology, diseases, and orthopaedics research. 

Each of the sections devoted to the five objectives features a major project or activity to highlight 

a significant NIAMS accomplishment in that area. A number of these highlighted projects also 

showcase the Institute’s leadership in collaborative activities to advance science. Leveraging 

partnerships has been a major strength of NIAMS, and we will continue to pursue this strategy to 

accomplish our research objectives. 

The new plan differs from previous NIAMS planning 

documents in two ways. First, it features four broad 

cross-cutting scientific themes that are relevant to all, or 

most, of the disease- and tissue-specific topics within 

the NIAMS mission. We chose these themes because 

they were heard across the “listening sessions” we held 

with representatives from each of our research areas. As 

such, research topics included in this section also appear 

throughout the disease- and tissue-specific sections both 

to provide additional detail in each of the areas and to 

ensure that these key points reach all audiences. These themes, which provide potential 

opportunities to better organize and conduct science across our mission areas, are: 

Aspirations 

Looking across the NIAMS 

portfolio, many reasons exist to be 

hopeful. Progress related to the 

cross-cutting themes is relevant to 

several diseases and conditions 

within the NIAMS mission. 

• Precision medicine for arthritis and musculoskeletal and skin diseases; 

• Shared mechanisms in health and among diseases; 

• Patient-centric approaches to health and disease; and 

• Health and disease in diverse populations. 

The themes focus on the increasing convergence of scientific knowledge and approaches across 

fields, which represents an unprecedented opportunity to invigorate the conduct of science. To 

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illustrate the potential of these areas, we have included several aspirations that provide examples 

of a vision for where cross-cutting, convergent research may lead us in the coming years or 

decades. Although NIAMS primarily funds individual investigator-initiated research projects, we 

encourage investigators to consider convergence with other scientific areas as they plan their 

own research and, when possible, to collaborate across disciplines. 

Second, the plan includes a new section that addresses National Institutes of Health (NIH) and 

NIAMS activities related to: 

• Priority setting; 

• Workforce recruitment, development, retention, and diversity; 

• Innovation; 

• Research partnerships; 

• Inclusion of diverse populations as participants in biomedical research; 

• Performance measures and assessment; and 

• Information dissemination and outreach. 

Including these topics in our Strategic Plan is a key step in sharing information with the research 

community and the public about our commitment to responsible management, stewardship, and 

accountability. Over the next 5 years we will continue to support and promote these initiatives 

while looking for additional opportunities to be even more transparent about the Institute’s 

efforts in these areas. 

Importantly, the development of this plan benefitted from the collective wisdom of members of 

both the scientific and lay communities interested in and affected by diseases and conditions 

within the NIAMS mission, and we thank all those who contributed their expertise and insights. 

We hope that the Fiscal Years 2020-2024 Strategic Plan will inspire those involved or interested 

in NIAMS research as investigators, research participants, patients, or the general public, and 

that it serves as a resource for all who have an interest in our mission. We encourage you to share 

the plan broadly with your colleagues. 

/Robert H. Carter/ 

Robert H. Carter, M.D. 

Acting Director 

National Institute of Arthritis and Musculoskeletal and Skin Diseases 

National Institutes of Health 

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EXECUTIVE SUMMARY 

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) advances 

health through biomedical and behavioral research, as well as through research training. The 

NIAMS mission is to support research into the causes, treatment, and prevention of arthritis and 

musculoskeletal and skin diseases; training of basic and clinical scientists to carry out this 

research; and dissemination of information on research progress in these diseases. 

The Institute’s research portfolio includes five core mission areas: (1) Systemic Rheumatic and 

Autoimmune Diseases; (2) Skin Biology and Diseases; (3) Bone Biology and Diseases; (4) 

Muscle Biology and Diseases; and (5) Joint Biology, Diseases, and Orthopaedics. Within these 

mission areas, NIAMS supports research at multiple levels, ranging from basic studies to enable 

comprehensive understanding of the molecular mechanisms underlying disease processes to 

preclinical research in model systems to translational studies to clinical and epidemiological 

research. In addition to research projects, NIAMS supports research training and career 

development, scientific conferences, and research infrastructure such as core facilities that 

enhance and accelerate NIH-funded research or research that is sponsored by other public and 

private organizations. The ultimate goal of these efforts is to develop patient-centered, 

personalized ways to improve outcomes and thereby “turn discovery into health.” 

The NIAMS Strategic Plan for Fiscal Years (FYs) 2020-2024 is a part of the Institute’s scientific 

planning process. The goal of the plan is to advance and accelerate research into the causes, 

treatment, and prevention of arthritis and musculoskeletal and skin diseases. The plan also serves 

as a platform to facilitate communication between the Institute and its many constituents— 

scientific communities, health care providers, health advocacy organizations, patients, the 

general public, and policymakers—about needs and opportunities related to the NIAMS mission. 

The plan is not intended to prescribe what investigators should pursue in their exploration of 

scientific problems that bear on the health of bones, joints, muscles, and skin. Rather, it is 

intended as a guide that might lead to unanticipated new scientific directions. As always, the 

Institute will continue to value and rely on investigator-initiated science as a critical source of 

innovation. 

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Cross-cutting scientific themes 

Although the plan includes research objectives related to the Institute’s five disease- or tissuespecific areas noted above, modern biomedical and behavioral research increasingly crosses 

those traditional disease- and tissue-specific boundaries. Many scientific challenges and 

opportunities within the NIAMS mission are not unique to any one field, disease, or scientific or 

clinical discipline. Therefore, the FYs 2020-2024 plan includes a new section highlighting crosscutting scientific themes relevant to many areas of the NIAMS mission. These themes, briefly 

outlined below, provide a framework for understanding the convergence of ideas, knowledge, 

and approaches across fields. 

Precision medicine for arthritis and musculoskeletal and skin diseases 

Emerging technologies, such as techniques to analyze single cells and innovative genomic 

approaches, have yielded a wealth of data that can be integrated with clinical information to 

build sophisticated new models of health and disease. In the coming years, these approaches, 

which give researchers powerful new tools to address longstanding research questions, are 

expected to advance knowledge in many NIAMS mission areas and yield more personalized 

treatments for patients. 

Shared mechanisms in health and among diseases 

Increasingly, researchers are discovering commonalities among seemingly disparate diseases and 

revealing how basic processes such as immunity, inflammation, regeneration, and metabolism 

play a role in maintaining health or, when perturbed, in the development of disease. The 

discovery of shared molecular, physiological, and behavioral components and mechanisms of 

action across different diseases is blurring the traditional boundaries of biomedical science and 

challenging investigators to employ new approaches to explore scientific questions. 

Patient-centric approaches to health and disease 

Over the past 5 years, efforts to integrate the patient perspective into research have progressed. 

New tools are available to capture patient-reported data for use in clinical trials and care. This 

integration offers promise for more holistic therapies to improve health and enhance the patient 

experience. 

Health and disease in diverse populations 

Different demographic groups often have distinct health concerns and disparities exist among 

groups with regard to health outcomes for diseases within the NIAMS mission. To achieve the 

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goal of improving human health, NIAMS-funded research must be applicable to health and 

disease in many populations. 

Management, scientific stewardship, and accountability 

In addition to the new focus on the cross-cutting scientific themes described above, the plan also 

includes a section dedicated to the Institute’s commitment to managing, accounting for, and 

providing stewardship of the public resources that support its mission. This component of the 

plan describes the ways in which NIAMS sets priorities and invests taxpayer funds strategically. 

Through various activities, NIAMS fosters the next generation of researchers in NIAMS mission 

areas, supports investigation of bold and innovative hypotheses, encourages the development and 

sharing of state-of-the-art resources, ensures the inclusion of diverse populations in biomedical 

research, and provides information to the public about NIAMS-funded scientific advances. 

Specific topics related to this commitment include the following. 

Priority setting 

NIAMS employs a standard process for making funding decisions, the cornerstone of which is 

peer review by the research community coupled with careful consideration by Institute 

leadership. This process helps to ensure that the Institute invests in highly meritorious research 

that addresses promising scientific opportunities and pressing public health needs. 

Workforce recruitment, development, retention, and diversity 

Biomedical and behavioral research is a human endeavor and NIAMS is committed to keeping 

the talent pipeline robust and diverse. Fostering early-stage investigators and supporting a range 

of research training and career development programs for mid-career clinicians and scientists are 

key NIAMS goals. 

Innovation 

New and highly innovative hypotheses and approaches play important roles in moving science 

forward. Although exploring such hypotheses may entail higher risk than pursuing research that 

builds incrementally, highly novel research has tremendous potential to advance scientific 

knowledge and expand technological capabilities. In addition to supporting trans-NIH efforts to 

foster innovation, NIAMS supports targeted initiatives to encourage paradigm-shifting research 

in its mission areas. 

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Research partnerships 

NIAMS works closely with other NIH components to advance research in areas of shared 

interest. Through participation in trans-NIH working groups the Institute ensures that diseases 

within its purview are included in trans-NIH initiatives and avoids duplication of effort with 

other NIH entities. Like all NIH Institutes, Centers, and Offices, in addition to managing its own 

budget allocation, NIAMS employs agency-wide approaches and resources, drawing from the 

NIH Common Fund and other resources available across NIH to support cross-cutting research 

and address infrastructure needs not unique to any given NIH component. NIAMS also continues 

to partner with a variety of public and private organizations to advance the transformation of 

discovery to health. Through these efforts, NIAMS leverages existing resources and explores 

numerous scientific areas in ways that it would be unable to tackle alone. 

Inclusion of diverse populations as participants in biomedical research 

NIAMS supports research to improve understanding about the unique health needs of women, 

children, older adults, minorities, and other groups and to address health disparities. This 

research is supported by tangible polices to ensure that women, racial/ethnic groups, and other 

populations are included as participants in NIAMS-funded clinical research. In addition, the 

Institute supports NIH-wide efforts to incorporate sex as a biological variable in preclinical 

research. 

Performance measures and assessment 

NIAMS uses quantitative and qualitative approaches to inform the development, conduct, and 

improvement of Institute programs. Through these careful assessments, the Institute enhances its 

efforts to further the ultimate goal of turning discovery into health. 

Information dissemination and outreach 

To maximize return on its investment in research, NIAMS encourages the dissemination of 

research findings to health care providers and the public. NIAMS will continue working closely 

with stakeholders to promote broad dissemination of scientific and health-related knowledge to 

the Institute’s varied communities. 

* * * * * * * * * * * * * * * 

Importantly, the NIAMS Strategic Plan for FYs 2020-2024 is a starting point, not a destination. 

While the plan is intended to provide a broad view of potential opportunities and challenges, 

research is likely to advance and evolve in many unanticipated ways over the 5-year period. The 

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Institute is committed to communicating transparently with its stakeholders about its future plans 

to maximize the careful stewardship of federal funds and to respond appropriately to emerging 

needs and opportunities in science and health. 

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INTRODUCTION, MISSION, AND STRUCTURE 

Introduction 

NIAMS supports research into causes, treatment, and prevention of arthritis and musculoskeletal 

and skin diseases; training of basic and clinical scientists to carry out this research; and 

dissemination of information on research progress in these diseases. It is critical to revisit 

program areas periodically because research needs, opportunities, and challenges change over 

time. The NIAMS Strategic Plan for FYs 2020-2024 will facilitate communication between the 

Institute and its many constituents—scientific communities, health care providers, health 

advocacy organizations, the general public, and policymakers—about needs and opportunities 

related to the NIAMS mission. 

Arthritis and musculoskeletal and skin conditions of all types affect people of all ages and of all 

racial and ethnic backgrounds. Combined, they afflict tens of millions of Americans, cause 

tremendous human suffering, and cost the U.S. economy billions of dollars in health care costs 

and lost productivity. Most of the diseases covered by the NIAMS mission areas are chronic and 

many cause lifelong pain, disability, or disfigurement. Diseases within the NIAMS mission also 

may lead to or be associated with the development of other serious medical conditions, referred 

to as comorbidities or co-occurring conditions. Some of these conditions are very common, 

while some are rare, affecting only a few thousand people worldwide. The 2017 Global Burden 

of Disease data have provided a wealth of information about the extent to which many of these 

conditions affect society. For example, in 2017, low back pain was the leading cause of 

disability in the United States, as measured in years lived with disability (YLDs).

1

 Other 

musculoskeletal diseases, a category that includes many systemic rheumatic, bone, muscle, and 

joint diseases, was among the top 10 causes of YLDs. The Centers for Disease Control and 

Prevention (CDC) estimate that 57.9 million adults in the United States have arthritis,

2 and a 

recent study suggests that this may be an underestimate.

3

 As the U.S. population ages, the 

prevalence of arthritis and its associated costs is expected to grow. 

1 The Institute for Health Metrics and Evaluation (IHME). (2017). United States. Available at 

http://www.healthdata.org/united-states 2 Centers for Disease Control and Prevention (CDC). National Center for Health Statistics. (2017). Arthritis. 

Available at https://www.cdc.gov/nchs/fastats/arthritis.htm 

3 Jafarzadeh SR, et al. Arthritis Rheumatol. 2018. PMID: 29178176. 

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Whether common or rare, many diseases and conditions within the NIAMS mission affect 

women and minorities disproportionately, both in increased numbers of those affected and 

increased disease severity. For example, findings from recent CDC-funded population-based 

systemic lupus erythematosus (SLE) registries in Alaska, California, Georgia, Michigan, and 

New York provide additional information about lupus health disparities. These and earlier 

studies show that women with SLE significantly outnumber men, and the disease is more 

common in African American, Hispanic, Asian, and American Indian women than in white 

women.

4

4 CDC. (2018). Lupus. Available at https://www.cdc.gov/lupus/funded/lupus-studies.htm 

 Furthermore, the CDC-funded research documents an earlier onset of lupus and higher 

burden of disease in African Americans than in whites.5 

5 Somers EC, et al. Arthritis Rheumatol. 2014. PMID: 24504809. 

6

6 Lim SS, et al. Arthritis Rheumatol. 2014. PMID: 24504808. 

 Rheumatoid arthritis, osteoporosis, and 

osteoarthritis (in people over 45 years of age) are also more prevalent among women, whereas 

certain forms of ankylosing spondylitis (inflammation of the joints in the spine) occur more 

frequently in men. 

Socioeconomic status, education level, cultural issues, and medical practice variation are all 

factors that may contribute to health disparities after disease onset, potentially affecting disease 

progression and treatment response. Understanding the role these factors play can inform the 

development of strategies to reduce outcome disparities, and that knowledge will enable early 

diagnosis and disease management tailored to an individual’s needs. 

In accordance with the 21st Century Cures Act (Public Law 114-255), enacted in 2016, the 

NIAMS Director consults with the Director of the National Institute on Minority Health and 

Health Disparities (NIMHD) and the Director of the Office of Research on Women’s Health 

(ORWH) regarding NIAMS objectives to ensure its future activities take into account the health 

needs of women and minorities and are focused on reducing health disparities. NIAMS works 

closely with NIMHD and ORWH, and NIAMS staff are active participants in standing and ad 

hoc committees related to NIH priorities for women’s health, minority health, and health 

disparities. These relationships enable the Institute to align its work in these areas with broader 

NIH efforts and to leverage and synergize with related activities across NIH. 

The goal of the NIAMS FYs 2020-2024 strategic plan is to advance and accelerate research into 

the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. Like the 

previous plans, it is expected to continue to promote exploration of ideas and encourage new 

research directions as needed. Although NIAMS expects to continue to devote the majority of its 

extramural budget to funding the most meritorious investigator-initiated research, the Institute 

recognizes the need for flexibility in serving the scientific community in the best possible ways. 

The plan brings attention to many areas that could be explored in coming years to stimulate 

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research progress related to improved understanding, diagnosis, treatment, and ultimately 

prevention of diseases within the NIAMS mission. 

The plan is not meant to be comprehensive; it does not mention every research area or disease of 

interest by name. As a broad scientific outline for NIAMS, however, it elaborates some of the 

Institute’s known areas of interest, while enabling the Institute to adapt to rapidly changing 

biomedical and behavioral science landscapes. 

Mission and Statutory Authority 

The Health Research Extension Act of 1985 (Public Law 99-158) authorized the establishment 

of NIAMS, which was formally established in 1986. The mission of NIAMS is to support 

research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin 

diseases; training of basic and clinical scientists to carry out this research; and dissemination of 

information on research progress in these diseases. 

NIAMS Organizational Structure 

NIAMS is one of 27 Institutes and Centers of NIH, the Nation’s premier biomedical research 

agency. NIH is the steward of medical and behavioral research for the Nation. The agency is 

responsible to Congress and the U.S. taxpayers for carrying out its mission to seek fundamental 

knowledge about the nature and behavior of living systems and the application of that knowledge 

to enhance health, lengthen life, and reduce illness and disability, in a manner that not only 

facilitates research but does so cost-effectively and in compliance with applicable rules and 

regulations. 

The NIAMS organizational structure includes an Office of the Director, which provides overall 

leadership for and administration of the Institute’s components, including the Division of 

Extramural Research (DER) and the Intramural Research Program (IRP). The NIAMS DER 

supports scientific studies and research training and career development throughout the country 

through grants and contracts to research organizations. The NIAMS IRP, located on the NIH 

campus in Bethesda, Maryland, conducts high-risk, high-reward basic, translational, and clinical 

research in NIAMS mission areas. 

The NIAMS Strategic Plan for FYs 2020-2024 focuses primarily on the Institute’s extramural 

program because the NIAMS intramural strategic planning process is linked to a larger NIHwide planning process for intramural research. Furthermore, the NIAMS IRP has a number of 

capabilities and resources that are purposefully different from, and complementary to, those 

supported by the NIAMS DER. The science conducted by the IRP has a more restricted focus 

than that of extramural research in part because of budgetary limitations, but also to focus on the 

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unique strengths of the IRP. For example, the IRP has a long tradition of excellence in long-term, 

high-risk research into the genetics and pathophysiology of human disease and the development 

of innovative therapies for a number of serious disorders for which satisfactory treatments 

previously did not exist. The IRP also has several distinctive characteristics, including: a unique 

funding model using a largely retrospective review of investigators to inform funding decisions; 

a concentration of interactive outstanding investigators in a collaborative environment with fluid 

boundaries between basic, translational, and clinical research; exceptional research resources, 

including the NIH Clinical Center; a longstanding culture of mentoring trainees at all levels; and 

a rich environment for training physician-scientists due to the presence of basic, translational, 

and clinical researchers. 

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CROSS-CUTTING SCIENTIFIC THEMES 

Many scientific challenges and opportunities within the NIAMS mission are not unique to any 

one field, disease, or scientific or clinical discipline. Rather, they transcend disease- and tissuespecific boundaries, have broad impact across many diseases and conditions, and can therefore 

serve as a framework to organize science across the assorted fields within the Institute’s purview. 

A commonality that links these themes is the concept of convergence science, which refers to the 

coming together of different scientific and technological fields to catalyze scientific progress. 

This section of the Strategic Plan describes the following four cross-cutting scientific themes: 

• Precision medicine for arthritis and musculoskeletal and skin diseases 

• Shared mechanisms in health and among diseases 

• Patient-centric approaches to health and disease 

• Health and disease in diverse populations 

Because they are cross-cutting, these themes resonate and create synergies with the scientific 

goals described in the disease- and tissue-specific sections of the plan. Many of the research 

areas described under these themes are addressed with greater specificity within those sections, 

depending on the stage of development of the field. For example, microbiome studies focus on 

mechanisms and effects of multiple microorganisms that are shared across many areas of health 

and disease, but such studies are more advanced in skin research than in many other areas. 

The cross-cutting scientific themes represent areas that might benefit from an overarching 

approach, for example, the development of multi- and interdisciplinary teams to advance 

research on tissue interactions. In some cases, they highlight a collective need across mission 

areas for shared complex technologies, for example, in vivo visualization of molecules or cells. 

They are often areas for which multiple diseases require the same methodological approach, such 

as extensive phenotyping to better characterize disease heterogeneity. They also reveal emerging 

scientific opportunities such as improved understanding of environmental triggers of disease 

initiation and progression. 

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NIAMS Aspirations 

Looking across the NIAMS portfolio, many reasons exist to be hopeful. The list below provides 

a few examples of advances that are possible during the next 5 years. These aspirations 

exemplify the broad concepts, for example, precision medicine, described under the cross-cutting 

themes. Importantly, this list is neither comprehensive nor exhaustive. Progress related to the 

cross-cutting themes is relevant to several diseases and conditions within the NIAMS mission. In 

addition, many unanticipated advances in a range of areas are likely to occur. Although unable to 

guarantee that all of these aspirations will be realized, these are areas in which the state of the 

science suggests a clear path forward. They are intended to convey the promise of the science 

and a vision for improving health and quality of life. 

 A gene therapy for muscular dystrophy or epidermolysis bullosa will restore the function 

of the missing or mutated gene and improve patient outcomes. 

 Biomarkers will guide the choice of the most effective therapy for each individual 

rheumatoid arthritis patient. 

 New nonsurgical treatments, including medical or regenerative medicine therapies, will 

be available to reduce pain and disability in patients with osteoarthritis. 

 Preventive therapy will delay the onset of autoimmune diseases like lupus and 

rheumatoid arthritis. 

 New personalized nonaddictive therapies will reduce chronic low back pain. 

 Clinical research will demonstrate the efficacy of intervention(s) to reduce disparities 

between minority populations and the general population in access to and use of existing 

surgical and nonsurgical interventions for osteoarthritis. 

 The number of fractures due to osteoporosis will decline as precision medicine allows 

treatment to be targeted based on the specific mechanism of bone loss occurring in a 

particular patient. 

Precision Medicine for Arthritis and Musculoskeletal and Skin 

Diseases 

The emergence of powerful new technologies and computational tools to measure and analyze 

biological mechanisms has advanced our understanding of the molecular basis of health and 

disease. These tools also present unique opportunities to realize the promise of precision 

medicine, that is, treatment targeted to an individual’s unique biology. Integrating multifaceted 

disease mechanism data with accurate and detailed clinical and patient-reported information 

offers new possibilities for understanding variations in symptoms, co-occurring conditions, and 

response to therapy among patients with the same diagnosis, and for precise targeting of disease 

pathways active in different patients. This integrated information could be used to identify 

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patient subsets, inform the development of new therapies, tailor the specific range of drugs now 

available to individual patients, and enhance risk-benefit assessments. 

Focus areas 

“Omics” at the tissue and single cell levels 

• Enhancing the use of multiple approaches to quantitation of genes, proteins, 

metabolites, and cellular and tissue pathways in physiologic and pathologic states 

• Determining global sets of molecular interactions, that is, the interactome, in cell 

types of interest 

• Promoting the application of advanced organ, tissue, and cellular structural and 

functional imaging technologies to collect data on normal and pathological states 

of tissues including bone, muscle, skin, and connective tissue 

Precision medicine in clinical research and clinical care 

• Applying “omics” to develop deep phenotyping7 of arthritis and musculoskeletal 

and skin diseases to improve understanding of disease heterogeneity and identify 

disease subtypes 

• Facilitating implementation and dissemination of deep phenotyping technologies 

and methods 

• Improving understanding of adaptive mechanisms that may contribute to health 

by allowing secondary pathways to compensate for the loss of primary ones 

• Leveraging natural history studies to determine the natural progression of disease 

and identify risk factors and markers of common and rare diseases within the 

NIAMS mission 

• Using -omics approaches to enable the development of new diagnostic tools 

• Enhancing the pipeline for development and validation of disease biomarkers and 

surrogate endpoints of disease 

• Applying gene editing techniques (e.g., CRISPER-Cas9) to develop gene 

therapies for genetic diseases 

7 “Deep phenotyping can be defined as the precise and comprehensive analysis of phenotypic abnormalities in 

which the individual components of the phenotype are observed and described.” See Robinson PN. Hum Mutat. 

2012. PMID: 22504886 

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Data science, computational science, and artificial intelligence 

• Aligning NIAMS efforts with strategies for managing big data included in the 

NIH Strategic Plan for Data Science, such as the FAIR (findable, accessible, 

interoperable, and reusable) data principles 

• Capitalizing on NIH data science infrastructure, tools, and resources, such as the 

Science and Technology Research Infrastructure for Discovery, Experimentation, 

and Sustainability (STRIDES) initiative to advance arthritis and musculoskeletal 

and skin diseases research 

• Identifying key research challenges and opportunities that can be uniquely 

addressed by focused efforts in artificial intelligence and computational science 

• Determining ways to enhance access to multidomain tissue and disease data 

Shared Mechanisms in Health and Among Diseases 

Several basic biological processes critical to maintaining or restoring health are common across 

dissimilar tissues and organ systems. For example, inflammatory, reparative, regenerative, and 

metabolic processes may be similar across tissues and are closely linked through the processes of 

immune system activation and stem cell stimulation. Sharing knowledge from research on one 

tissue system could inform investigations of others and lead to better understanding of the role of 

basic biological processes in promoting health or causing disease across a number of tissues. 

Because perturbations of these basic processes can lead to disease, comparisons among diseases 

could provide researchers with new insights into potential mechanisms and therapeutic targets. 

Focus areas 

Immunity and inflammation 

• Understanding the role of immune cells in the maintenance of normal homeostasis in 

tissues, for example, skin, bone, connective tissue, and muscle 

• Exploring the role of immune responses and inflammation in genetic and acquired 

diseases of skin, bone, joint, and muscle 

• Investigating the role of inflammation in disease onset, progression, or recovery and 

healing in genetic and degenerative diseases of bone, joint, muscle, and skin 

• Studying immune and inflammatory targets in the treatment of genetic and 

degenerative bone, joint, muscle, and skin diseases 

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Regenerative medicine: Wound healing, tissue repair, and regeneration 

• Identifying common pathways involved in wound healing and tissue regeneration 

• Dissecting repair and regeneration processes, including maladaptive repair responses 

like fibrosis and sclerosis 

• Expanding research on stem cell therapy and other emerging approaches like plateletrich plasma treatments for musculoskeletal injuries to provide a scientific basis for 

enhancing their effectiveness and safety 

• Encouraging the use of multidisciplinary teams and integrative approaches to 

investigate cell-cell, tissue-tissue, and cell-extracellular matrix interactions critical to 

maintaining and restoring structure and function 

• Advancing research on the biology of junctional tissues such as the enthesis and 

associated transitional areas between tissues to inform the development of clinical 

approaches and improve outcomes for diseases within the NIAMS mission 

Neurosensory aspects, including pain and itch 

• Identifying the relative contribution of nociceptive, neuropathic, and central pain and 

the role of itch mechanisms in chronic conditions and the shared and distinct 

pathways involved in pain and itch 

• Exploring the relationship between pain, itch, and inflammation in both acute and 

chronic diseases within the mission of NIAMS 

• Investigating the relationships among pain, itch, and function to understand how their 

intersections contribute to disability 

Effects of environmental exposures 

• Improving understanding of the role of the microbiome in normal tissue development 

and homeostasis and during disease and recovery 

• Identifying chemical and physical exposures that may increase susceptibility to 

disease and understanding how these factors affect onset and severity of disease 

• Enhancing research on the effects of nutrients, diet, and exercise on health and as 

adjuncts to treatment 

• Studying gene-environment interactions 

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Metabolism 

• Studying the roles of skin, muscle, bone, connective tissue, and the immune system in 

maintaining balanced body metabolic rates (homeostasis) 

• Determining the metabolic pathways that affect cell proliferation, function, and 

senescence using technologies such as metabolomics, lipidomics, and glycomics 

Patient-Centric Approaches to Health and Disease 

Clinical research plays a vital role in translating basic knowledge into interventions to improve 

health. Researchers are developing innovative approaches to clinical research that incorporate 

existing patient data systems and other emerging resources. At the same time, there is growing 

recognition and awareness of the role of biopsychosocial factors as important contributors to 

both disease manifestations and responses to interventions. Careful analysis of patient 

characteristics as well as particular patterns of disease in a specific person (endotype), including 

patient-reported symptoms and preferences, will contribute to development of therapies 

personalized for the individual patient. The PROMIS® (Patient-Reported Outcomes 

Measurement Information System), described below, is an example of one tool to capture a 

patient’s daily quality of life through self-reporting. Finally, including patients and their 

caregivers as partners in the design and implementation of research projects, including the 

development of research questions, directions, priorities, and outcome measures, will be critical 

to the success of efforts to improve the development and testing of new therapies. 

Patient-Reported Outcome Measures: Incorporating the Patient Perspective 

There are many ways to clinically measure a patient’s health status, such as through blood tests 

and X-rays. However, these may not capture features that affect daily quality of life, such as pain 

and fatigue. To address the need to incorporate patient input into clinical research and care, NIH 

is advancing patient-reported outcome (PRO) measures. These efforts, including the Patient 

Reported Outcomes Measurement Information System (PROMIS®)1, grew out of an NIH 

Common Fund initiative2 administered by NIAMS. The initiative supported the development and 

validation of a wide range of psychometrically and clinically robust instruments to gather 

information on health-related concerns, such as pain, fatigue, and physical functioning, across a 

wide range of disorders in adults and children. PROMIS adult and pediatric measures are being 

adapted for use across numerous diseases, languages, literacy levels, and ethnic groups. Patients 

can report their information in a variety of settings, including by phone or online. Today, the 

tools are being used to assess symptoms and measure changes over time and in response to 

treatment in both clinical trials and patient care settings both nationally and internationally. The 

measures are helping to better tailor and monitor treatments and understand diseases and their 

21 
 

 

 

 

 

impact on patients’ symptoms, functioning, and quality of life. NIAMS is encouraging the use of 

these tools to foster patient-centric care for diseases within its mission. 

Although the original Common Fund initiative that spurred the development and validation of 

PROMIS and other PRO measures has ended, the program has successfully shifted to a sustained 

research effort supported by a trans-NIH cooperative agreement. Current work is advancing the 

science of PRO measures (PRO-omics) and facilitating their integration in complementary and 

meaningful ways with other ‘omics’ (e.g., transcriptomics) data that assess a person’s disease 

and health status. Some of the available measures are designed to assess a specific disease or 

condition, while others, such as PROMIS, are applicable to many different conditions and can 

therefore be used to facilitate within or across disease comparisons. 

PRO measures increasingly are being adopted for use in pediatric populations. For example, 

NIAMS administers the Pediatric Patient Reported Outcomes in Chronic Diseases (PEPR) 

consortium3

, an initiative that capitalizes on recent advances in PROMIS pediatric measures to 

assess the health of children with a variety of chronic diseases and conditions in clinical research 

and care settings. The PEPR tools are informing and supporting the NIH Environmental 

Influences on Child Health Outcomes Program4 to capture the perspectives and experiences of 

children and their families who are participating in this groundbreaking pediatric consortium. 

For further information see: 

1 The Patient Reported Outcomes Measurement Information System (PROMIS®) webpage. 

2 The Common Fund PROMIS® webpage. 

3 Information about the Pediatric Patient Reported Outcomes in Chronic Diseases (PEPR) 

consortium. 4 The Environmental Influences on Child Health Outcomes Program website. 

Focus areas 

The patient experience 

• Advancing the development, validation, and use of patient-reported outcomes in 

clinical trials and longitudinal studies within the NIAMS portfolio 

• Promoting development and testing of measures, wearable devices, and biosensors to 

assess physical function and other outcomes 

• Encouraging research on patient preferences to identify the most important benefits of 

interventions, understand barriers to implementing prevention and treatment 

approaches, provide evidence for risk/benefit assessments, and identify variability of 

preferences at the individual and population levels 

22 
 

 

 

 

• Using information about biological mechanisms to inform the development of 

individualized and multimodal diagnostic and treatment algorithms for pain 

management 

• Improving understanding of biopsychosocial (e.g., sensory, cognitive, and affective) 

components of pain to understand the distinction between tissue damage and the 

experience of pain 

• Promoting development and testing of approaches tailored to preventing or treating 

co-occurring conditions 

• Advancing dissemination and implementation research and methods to encourage the 

application of evidence-based practices in health care settings 

• Encouraging research that incorporates rehabilitation science, including patientcentered rehabilitation approaches, in the study of diseases and conditions within the 

NIAMS mission 

Innovative approaches to clinical trials 

• Encouraging the development of trials targeting preclinical disease to develop 

effective strategies for disease prevention 

• Promoting the use of new methodologies, emerging research frameworks, and 

innovative resources, such as linking to the electronic medical record, in clinical 

studies to achieve greater efficiency and effectiveness 

• Using molecular signatures and biomarkers to better stratify and classify patients for 

participation in clinical trials 

• Leveraging clinical research resources, such as those in the Clinical and Translational 

Science Awards program, to test new trial designs 

• Engaging key stakeholders in the health care provider and patient communities to 

enhance the application of trial results to medical practice 

• Improving clinical trial design and recruitment to increase participation of 

populations of diverse ancestral backgrounds, including encouraging communitybased participatory research and addressing barriers that discourage participation of 

diverse groups 

• Facilitating natural history studies and observational studies to improve 

understanding of early disease processes, risk factors for disease, and disease 

transitions 

Health and Disease in Diverse Populations 

Research funded by the Institute is relevant to a number of populations, including groups 

historically underrepresented in biomedical research. NIAMS supports research to explore 

23 
 

 

 

 

biological, mechanistic, environmental, biopsychosocial, cultural, and other factors that affect 

the health of specific populations and how these factors may differ among groups, the 

interactions among these factors, and their potential contribution to health outcomes. The next 5 

years offer exciting opportunities to develop interventions that could improve health and reduce 

health disparities. For example, the interface between patients and the health care system is 

emerging as an important area of research, and more is being learned about how an individual’s 

background affects communication with health care providers, perception of the risks and 

benefits of treatments, and individual patient preferences. Ultimately, NIAMS-funded research 

seeks to provide evidence to achieve health equity for all populations. 

Focus areas 

Health research in diverse groups 

• Pursuing research on diseases with significant effects on the overall health and quality 

of life of populations that have been underrepresented in biomedical research 

• Investigating genetic, biological, and environmental mechanisms of disease in 

different racial, ethnic, and other underrepresented groups, as well as between the 

sexes and across the lifespan 

• Studying the influence of social determinants of health in different populations 

• Using novel methodologies to dissect the biological and biopsychosocial factors 

contributing to the observed greater prevalence in women of diseases like lupus and 

osteoporosis 

• Expanding research to improve understanding of the causes and long-term 

consequences of chronic and genetic diseases in children 

Health disparities research 

• Investigating genetic, biological, and environmental mechanisms, as well as social 

determinants contributing to health disparities (e.g., greater susceptibility to or 

increased severity of disease) 

• Exploring how health disparities may be related to symptom descriptions provided by 

patients, unconscious bias or lack of cultural competency of health care providers, or 

variability in treatment response 

• Understanding how comorbid (co-occurring) conditions may contribute to health 

disparities 

• Understanding how sex differences may contribute to health disparities between men 

and women in diseases of the bones, joints, muscles, and skin 

• Expanding use of health care data sources, such as electronic medical records and 

administrative databases (e.g., billing and pharmacy) to study health disparities 

24 
Effective therapies across diverse populations 

• Testing interventions to reduce health disparities by improving health in all 

populations 

• Incorporating findings from behavioral research to develop effective patient 

education strategies to promote adoption of healthy behaviors among diverse groups 

• Examining ways that treatment protocols and interactions with health care providers 

and systems could be modified to better serve diverse populations (e.g., to encourage 

the appropriate use of total joint replacement for all populations) 

• Advancing dissemination and implementation research focused on improving the 

uptake of research findings in diverse communities to improve health 

25 
 

 

DISEASE- AND TISSUE-SPECIFIC SCIENTIFIC OBJECTIVES 

The goal of the NIAMS FYs 2020-2024 strategic plan is to advance and accelerate research into 

the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. The plan 

includes five objectives to advance and accelerate: 

• Systemic rheumatic and autoimmune diseases research; 

• Skin biology and diseases research; 

• Bone biology and diseases research; 

• Muscle biology and diseases research, and 

• Joint biology, diseases, and orthopaedics research. 

The following sections describe NIAMS objectives in each of these five areas. These objectives 

focus on research to understand basic mechanisms of biological processes, investigations of the 

genetic and environmental causes of disease, preclinical research to translate new knowledge 

into potential therapies, and clinical research to assess the efficacy or new interventions. 

Research related to the objectives includes hypothesis-driven research as well as discovery 

research depending on the stage of the research field and ability of the scientific approach to shed 

light on a particular research question. Many topics described in the preceding section on crosscutting scientific themes are addressed more comprehensively in these sections. 

Although much of the arthritis and musculoskeletal and skin diseases research landscape falls 

within the NIAMS mission, some is included in the missions of other NIH components. In 

practice, the NIAMS collaborates closely with other NIH Institutes, Centers, and Offices in these 

areas of shared interest to achieve synergies and avoid duplication of effort. Research areas that 

clearly fall outside of the NIAMS mission (e.g., cancer) are generally not included in this 

strategic plan. 

As part of NIH, NIAMS is focused on the discovery of new biological knowledge and its 

application to improve human health. NIAMS helps to generate the evidence needed to advance 

new and improve existing treatments. Because the agency’s mission does not cover the entire 

healthcare continuum, the Institute works with partners in other Federal agencies, professional 

and patient groups, and industry to speed the translation of NIAMS-funded research. 

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Advancing and Accelerating Systemic Rheumatic and Autoimmune 

Diseases Research 

NIAMS Systemic Rheumatic and Autoimmune Diseases programs address basic, translational, 

and clinical research, including clinical trials and observational and mechanistic studies, focused 

on immune-mediated arthritis and autoimmune-related acute and chronic disorders in adults and 

children. As noted in the introduction to this plan, many of these diseases disproportionately 

affect women and groups historically underrepresented in biomedical research. While the 

underlying causes for these differences are largely unknown, progress is occurring in 

understanding them and translating that knowledge into effective treatments. 

The results of NIAMS-funded research have paved the way for biologic therapies for systemic 

rheumatic and autoimmune diseases. These therapies have improved outcomes and quality of life 

for many patients, highlighting the importance of fundamental research in improving health. 

Going forward, NIAMS will continue to build on this progress to further understanding of 

systemic rheumatic and autoimmune diseases and to develop even more effective and 

personalized treatment approaches. 

In adults, systemic rheumatic and autoimmune diseases and disorders include, but are not limited 

to: 

• rheumatoid arthritis; 

• systemic lupus erythematosus (or lupus); 

• crystalline-induced diseases (gout, calcium pyrophosphate dihydrate crystal deposition 

disease, hydroxyapatite crystal disease); 

• spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis); 

• reactive, enteropathic, and infectious arthritis; 

• systemic scleroderma and related conditions such as interstitial lung disease and 

Raynaud’s phenomenon; 

• vasculitides (giant cell arteritis, polymyalgia rheumatica, granulomatosis with 

polyangiitis); 

• Sjögren's syndrome; and 

• fibromyalgia syndrome. 

Pediatric diseases include all forms of juvenile idiopathic arthritis (JIA), childhood-onset lupus, 

scleroderma-related diseases, pediatric fibromyalgia, and periodic fever syndromes and other 

autoinflammatory disorders. Several aspects of these diseases differ between adults and children 

(e.g., risk factors, pathogenesis, outcomes), and these factors require special attention when 

conducting research on pediatric conditions. 

27 
 

 

 

 

 

 

 

 

Genetics, functional genomics, and epigenetics 

Rheumatologists have long recognized the higher incidence of many rheumatic diseases within 

families and certain ethnic populations, suggesting that genetics play a role in risk. Perseverance 

in gathering biospecimens and clinical histories from patients and their relatives—along with the 

explosion of knowledge and technological advances in genetics and genomics—have opened 

new research avenues. 

Functional genomics, gene regulation, epigenetics, and gene-environment 

interactions 

Genome-wide association studies (GWAS) and other genomic approaches, such as whole 

genome or exome sequencing, have identified a series of genes and gene polymorphisms, also 

referred to as genetic variants, that relate to disease risk and severity in different populations. 

Some of these polymorphisms point to common gene regulatory elements that may be shared in 

many autoimmune diseases. The discovery of genetic variants, most of which reside within nonprotein-coding regions of the genome, has advanced understanding of disease mechanisms, 

facilitated identification of potential pathways to target for therapy, and improved the assessment 

of disease risk. Despite progress in understanding some of the genetic variants involved in 

autoimmune and systemic rheumatic diseases, and in genomics approaches that have identified 

tens of thousands of genetic variants, the functional significance of most variants remains largely 

unknown. Follow-up studies are needed to understand how they may interact with each other, 

regulate expression and activity of target genes, and contribute to changes in cell functions and 

cell biology in ways that may affect disease risk and pathology in disease target tissues. 

Environmental factors (e.g., gut microbes, dietary components, chemicals, ultraviolet light, 

infectious agents) may interact with the host by influencing gene activities or turning on or off 

genes to affect an individual’s risk for diseases such as lupus, rheumatoid arthritis, and 

scleroderma. Environmental factors influence disease risk by interacting with the genome to alter 

gene expression without changing the underlying DNA. Analyses of these epigenetic changes, as 

well as genetics and transcriptomic data, are expected to provide novel insights into the 

development, progression, and severity of rheumatic diseases. 

Broad areas of potential research directions include: 

• Developing machine learning methods that combine layers of ‘omics data (e.g., 

genomics, proteomics, metabolomics) to generate new mechanistic hypotheses and 

inform discovery of novel drug targets; 

• Applying novel approaches to study the function of genetic variants, including novel 

gene editing techniques (e.g., CRISPR/Cas9), to assess the functional effects and 

28 
 

 

 

 

 

 

 

 

 

 

therapeutic potential of candidate variants (enhancers, promoters, noncoding RNA) and 

epigenetic regulation in relevant cells, model systems (e.g., induced pluripotent stem 

cells), and in knockin or knockout (e.g., RNAi) in vitro and in animal models; 

• Understanding epigenetic mechanisms that link genotype to phenotype in rheumatic

diseases;

• Extending genetic and genomic studies to understudied ancestral populations (e.g., nonEuropean) to better understand the biological basis underlying differences in disease

susceptibility;

• Applying scalable, single-cell analysis approaches, such as parallel analyses of proteins

and gene expression and the epigenetic landscape in the same sample, to enhance

understanding of disease by analyzing large numbers of samples;

• Leveraging novel spatial multi-omics tools and approaches developed by the Human

BioMolecular Atlas program to further map molecular and cellular interactions in healthy

and disease tissues; 

• Applying novel strategies to dissect the major histocompatibility complex loci associated

with rheumatic diseases; and

• Studying gene-gene, gene-protein, and gene-environment interactions using novel or

enhanced analytic approaches.

Translation of genetic and genomic research from bench to bedside

The rapidly progressing fields of genetics and genomics offer powerful tools for drug discovery 

and for investigating the influence of genomic variations on drug responses, including drug 

efficacy and toxicity. The application of genomic approaches to well-characterized longitudinal 

clinical cohorts holds great promise for development of personalized medicine for systemic 

rheumatic and autoimmune diseases. 

Broad areas of potential research directions include: 

• Leveraging well-characterized patient cohorts and tissue repositories, along with novel

and robust genetic and genomic approaches, to understand the underlying mechanistic

differences in treatment responses and drug toxicities;

• Integrating genetic and genomic information to improve clinical trial design;

• Defining disease heterogeneity at the molecular level by applying genetic and functional

genomic information, as well as other relevant factors, to foster refinement of phenotypes

and subcategories of complex diseases;

• Translating genetic and genomic information into clinically actionable algorithms to aid

in identifying individuals at high risk for disease and to improve clinical diagnosis,

prognosis, treatment selection, compliance, and health-related quality of life;

29 
 

 

• Developing high-throughput methods to screen existing or novel molecules and drugs for 

targeting genetic/genomics-associated pathways with rapid transition to proof-of-concept 

trials; and 

• Exploring novel approaches in pharmacomicrobiomics (a subfield of genomics, 

microbiomics, and pharmacology) to understand the effects of the interaction between 

xenobiotics or foreign compounds and the gut microbiome on treatment responses and 

toxicities in systemic rheumatic and autoimmune diseases. 

Mechanisms of disease 

Innate and adaptive immunity 

Increased knowledge of basic functioning of the immune system, and in particular, the 

fundamental biology of autoimmunity, has advanced our understanding of systemic rheumatic 

and autoimmune diseases. The two arms of the immune system—the innate and adaptive arms— 

coexist as protective and potentially injurious forces. Successful immune response depends on 

the body’s ability to produce diverse receptors on the surface of immune cells. The innate 

immune system is the body’s first line of defense and reacts quickly and broadly to 

environmental or pathogenic insults to the body. It consists of anatomical barriers, networks of 

soluble mediators, and effector cells. In contrast to the innate immune system, the adaptive 

immune system provides more specific, targeted, and sustained responses. Because of the 

enormous number of antigens that the body routinely encounters and their potential similarity to 

the body’s own components, the adaptive immune system is at risk of producing self-reactive 

(autoreactive) cells that can trigger autoimmunity. The process of immune tolerance addresses 

this problem by either removing autoreactive cells from the system or by diminishing their 

reactivity enough to prevent disease. When there is a breach or dysregulation in immune 

tolerance, autoimmune disease can occur. Improved understanding of the immune system, the 

complex interplay between innate and adaptive immunity, as well as interactions between the 

immune system and various tissues in normal and pathological conditions will enhance 

development of antigen-specific and/or autoreactive, personalized, cell-specific therapies that 

leave protective, global immune function intact. 

Broad areas of potential research directions include: 

• Studying the role of innate immune system components—DAMPs, PAMPs, PRRs, 

inflammasomes, and associated signaling pathways—in the initiation and propagation of 

autoimmune and autoinflammatory diseases; 

• Expanding understanding of cross-regulation between components of the innate and 

adaptive immune systems in inflammation and rheumatic diseases; 

30 
 

 

 

 

 

 

 

 

• Studying involvement of a wide range of hematopoietic and other cell types in rheumatic 

diseases. Examples include—but are not limited to—macrophages, monocytes, 

neutrophils, platelets, dendritic cells, innate lymphoid cells, natural killer cells, mast 

cells, basophils, eosinophils, fibroblast, and synoviocytes; 

• Exploring the role of stem and progenitor cells in immune and autoimmune processes; 

• Applying single-cell analyses to further define the role of cell subsets and functional 

plasticity in innate and adaptive immune responses and autoimmune rheumatic diseases 

(e.g., diversity and plasticity of the monocyte-macrophage lineage in promoting or 

resolving inflammation, role of T and B cell subsets); 

• Understanding the contribution of dysregulated cellular processes (e.g., citrullination, 

programmed cell death, autophagy, unfolded protein response, mitochondrial 

dysfunction) and altered metabolism in development and progression of autoimmune 

disorders and autoinflammatory diseases; 

• Clarifying the role of the major histocompatibility complex and antigen-presenting cells 

in autoimmunity; 

• Developing novel techniques to identify autoantigens involved in rheumatic diseases; 

• Defining and characterizing mechanisms that control tolerance to self and autoantibody 

production; 

• Exploring mechanisms of remission and exacerbation of autoimmune diseases; 

• Investigating the diverse roles of B cells in autoimmune diseases, including autoantibody 

production; antigen presentation and co-stimulation during initiation of immune 

response; and the release of inflammatory and immunomodulatory cytokines; 

• Elucidating mechanisms by which sex-specific factors, such as sex hormones, sexspecific gene products (e.g., X and Y chromosome products), and other factors (e.g., 

pregnancy) influence immune functions to understand why autoimmunity is much more 

common in women; and 

• Understanding the cellular and molecular mechanisms linking cancer and autoimmune 

diseases, both in terms of autoimmunity increasing the risk of cancer and autoimmune 

adverse events stemming from checkpoint inhibitor therapies. 

Inflammation 

Chronic inflammation is a characteristic of many autoimmune and autoinflammatory diseases, 

including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic 

arthritis, inflammatory myopathies, and lupus. Inflammation likely causes or exacerbates joint 

swelling, acute and chronic pain, fatigue, sleep disorders, depression, and organ damage. 

Research advances detailing molecular and cellular contributors to inflammation have provided 

critical insights into potential causes and the development of therapeutics in many rheumatic 

diseases. 

31 
 

 

Broad areas of potential research directions include: 

• Identifying and characterizing molecular mechanisms that either resolve or dampen 

inflammation (e.g., anti-inflammatory cytokines, chemokine/chemokine receptors and 

“decoys,” lipid-derived mediators, leukocyte apoptosis); 

• Conducting further research on the role of immune cell subsets (e.g., T cells, B cells, 

dendritic cells, innate lymphoid cells) in the inflammatory processes in rheumatic 

diseases (e.g., the role of regulatory T cells in ameliorating inflammation); 

• Investigating the influence of immune-cell trafficking on disease mechanisms, including 

the identification of key components of leukocyte migration from the vasculature to 

surrounding tissues (extravasation), and examining the roles of the adhesion molecules 

and chemo-attractants that mediate cell trafficking; 

• Exploring the biology of neural regulation of immunity and inflammation and the 

therapeutic implications of those mechanistic insights for rheumatic and 

autoinflammatory diseases; and 

• Enhancing understanding of the genetics and mechanisms of autoinflammatory disorders 

(e.g., role of cytokines such as IL-1 and TNF-alpha) to improve diagnosis and treatment 

of these diseases. 

Pain 

Pain is one of the most important symptoms affecting quality of life for patients with rheumatic 

diseases and chronic pain syndromes. Research on the biological mechanisms of pain in 

rheumatic diseases may lead to new approaches to manage pain. 

Broad areas of potential research directions include: 

• Investigating interactions involving the plasticity of the peripheral and central nervous 

systems, and the plasticity of the inflammatory system, that may contribute collectively to 

the development and perpetuation of chronic pain through its centralization; 

• Implementing and comparing validated, universal, and disease-specific pain measures 

(e.g., PROMIS pain interference, behavior, quality, and intensity in pediatric and adult 

patients); 

• Gaining a better understanding of both peripheral and central mechanisms contributing to 

chronic musculoskeletal pain and the transition from acute to chronic pain; 

• Understanding how chronic inflammation may affect the brain and development of 

complex pain syndromes; 

• Characterizing reversible and permanent biochemical, inflammatory, autoimmune, and 

anatomic changes that cause or are caused by chronic pain; 

32 
 

 

 

• Identifying a set of biological, behavioral, genetic, epigenetic, cognitive, psychological, 

and social factors that make an individual susceptible to chronic pain, cause the transition 

from acute to chronic pain, or influence long-term outcomes of pain that begins in 

childhood; 

• Studying the heterogeneity and epidemiology of pain syndromes to understand their 

genetic, epigenetic, environmental, and social risk factors, the mechanisms by which they 

develop, and variations in phenotype; 

• Exploring and validating both existing and new tools that will allow for accurate 

diagnosis and optimized, personalized treatment of chronic pain conditions for both adult 

and pediatric populations; 

• Exploring the use of appropriate animal models of chronic pain to better understand its 

pathophysiology and etiology and to develop behavioral measures; 

• Developing novel therapeutic approaches to treat chronic pain conditions that encourage 

the development of analgesic drugs (including non-opioid-based drugs), personalized 

therapeutics, and behavioral interventions to improve both pain and related comorbidities 

such as fatigue, depression, and sleep disturbance; and 

• Leveraging imaging and other biomarkers to better understand the mechanisms of acute 

and chronic pain to facilitate future novel treatment approaches. 

Target organ damage 

Manifestations of rheumatic diseases can be diverse and may affect many organs and organ 

systems, including skin, joints, and other internal organs such as the kidneys, heart, lungs, 

intestines, blood vessels, and brain. Although immune dysregulation plays a major role in these 

diseases, the structure and function of target organs such as the vasculature may contribute 

significantly to the development of tissue damage and fibrosis in clinical disease. A better 

understanding of mechanisms of tissue damage may suggest how to modify contributing factors 

and lead to approaches to minimize or prevent some of the most serious complications of 

autoimmune disease. 

Broad areas of potential research directions include: 

• Applying single-cell analysis and spatial multi-omic approaches to study cells and 

molecules present in target tissues or organs (e.g., synovium in rheumatoid arthritis; 

kidneys in lupus; skin, lung, and other organs in scleroderma); 

• Exploring interrelationships between immune response components (both innate and 

adaptive) and target tissues or organs in normal and pathological conditions; 

• Characterizing and understanding how autoantibodies cause disease and tissue damage; 

• Investigating the role of nonimmune mechanisms (e.g., hypoxia, metabolic changes) in 

tissue injury; 

33 
 

 

 

 

 

• Exploring the role and mechanism of fibrosis in rheumatic diseases and the development 

of rheumatic disease-associated comorbidities (e.g., interstitial lung diseases, pulmonary 

hypertension, renal manifestations); 

• Investigating the role of altered cellular homeostasis (e.g., extracellular matrix 

components, gut microbiome) in the development of inflammatory and autoimmune 

diseases; 

• Characterizing the role of genetic factors in influencing the presentation and severity of 

disease in target organs; 

• Elucidating the effector mechanisms of tissue damage (e.g., complement, cytokines, and 

immune complexes); 

• Investigating how organ responses may sustain inflammatory disease; 

• Identifying associations between chronic inflammation and the initiation, progression, 

and treatment of cardiovascular disease in arthritic and rheumatic diseases; 

• Investigating the role of cellular senescence and aging in the development of end-organ 

tissue damage and resolution; 

• Studying the effect of symptom- and disease-modification-based therapies on organ 

damage; 

• Investigating the role of the synovial entheseal complex in spondyloarthropathies; 

• Studying the mechanisms of non-erosive inflammatory arthritis and musculoskeletal 

complications; 

• Understanding the roles of blood vessels and vascular endothelium in the pathogenesis of 

inflammatory rheumatic diseases; and 

• Investigating the function of neurons that innervate lymphoid tissues, and characterizing 

links between immune dysfunction and nervous system involvement in rheumatoid 

arthritis, lupus, scleroderma, and other rheumatic diseases. 

Preclinical and translational research 

Unraveling the complexity of rheumatic diseases to advance the development of effective and 

targeted interventions requires an understanding of how disease initiation and progression are 

integrated. Much of this research is conducted in model systems that lead to further refinement of 

therapeutic approaches and design before human testing. 

Recent progress in developing molecular and genetic tools for basic research (e.g., single-cell 

analysis, ‘omics technologies, genome editing, and sequencing techniques for identifying 

bacterial isolates) has facilitated disease-specific investigations. Preclinical and translational 

studies are expected to advance knowledge of underlying mechanisms and facilitate development 

of therapies for application in clinical practice. 

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Model systems 

Model systems aim to define disease mechanisms, as well as to design and test approaches to 

prevent disease onset and progression. Animal models offer some of the best systems available 

for detailed phenotyping of various diseases and conditions, enabling scientists to identify human 

disease-related genes and gain a better understanding of how these disease genes function. 

Current mouse models focus on immune-cell function and can recapitulate many aspects of 

human diseases (e.g., rheumatoid arthritis and lupus), which provides important information 

about pathogenic and therapeutic pathways and their interactions. Ex vivo or in vitro human cellbased systems may also serve as important experimental models for studying systemic rheumatic 

and autoimmune diseases. 

Given the complexity of immune responses, etiologic and mechanistic questions about disease 

are difficult to answer. By integrating large amounts of research data into dynamic computerbased models, systems biology approaches can be used to better understand, over time, 

interrelationships and regulation of various immune system components. 

Broad areas of potential research directions include: 

• Developing clinically relevant animal models for functional and mechanistic studies of 

pathogenic pathways identified by human genetic research; 

• Developing animal models that recapitulate molecular abnormalities identified in people 

with autoimmune diseases to improve understanding of disease mechanisms; 

• Developing and using humanized mouse models that more closely recapitulate the human 

immune system to identify mechanisms important for human disease and test 

therapeutics; 

• Using gene-modulation techniques (e.g., CRISPR/Cas9 for genome editing) to conduct 

large screens for phenotypes relevant to systemic rheumatic and autoimmune diseases 

(see also Genetics, Functional Genomics, and Epigenetics, above, for more information); 

• Combining animal models of human rheumatic diseases with systems biology approaches 

to identify critical cellular and molecular pathways involved in disease causation and to 

facilitate the identification of therapeutic targets (possible areas include central nervous 

system-endocrine-immune interactions that contribute to disease mechanisms and clinical 

symptoms); 

• Developing models for chronic manifestations of disease; and 

• Leveraging novel tissue engineering approaches to develop new model systems and 

improve existing complex in vitro, ex vivo, and organ model systems (i.e., threedimensional models) for studying systemic rheumatic and autoimmune diseases. 

35 
 

 

 

Therapy development 

Advances in immunology, molecular biology, and genetics are yielding an emerging set of 

therapies for systemic rheumatic and autoimmune diseases. The goal of NIAMS-supported 

research is multifold: ensure a continuous supply of new targets for intervention, understand 

mechanisms of action of new and existing drugs, and develop adequate clinical trial 

methodologies to test these interventions. The Accelerating Medicines Partnership, described in 

the box “Progress in Accelerating New Therapies for Rheumatoid Arthritis and Lupus,” is an 

example of a program NIAMS has used to ascertain and define shared and disease-specific 

biological pathways that researchers can study to identify relevant drug targets for treating 

autoimmune diseases. 

Progress in Accelerating New Therapies in Rheumatoid Arthritis and Lupus 

To increase the number of new diagnostics and therapies and reduce the time and cost of 

developing them, NIAMS is participating in the Accelerating Medicines Partnership (AMP) , a 1

collaboration among NIH, the Foundation for the NIH (FNIH), the U.S. Food and Drug 

Administration (FDA), biopharmaceutical companies, and nonprofit organizations. NIAMS, in 

partnership with the National Institute of Allergy and Infectious Diseases, contributes to the 

AMP in two disease areas: rheumatoid arthritis and lupus. The AMP in rheumatoid arthritis and 

lupus research network focuses on immune and tissue resident cells from organs affected by the 2

diseases, including cells from the joints of individuals with rheumatoid arthritis and from the 

kidneys and skin of people with lupus. The network is adapting cutting-edge technologies to 

allow those cells to be analyzed individually using high-throughput approaches. At the same 

time, the network has pioneered important innovations in the conduct of research, including new 

models for collaboration among dispersed research institutions, groundbreaking strategies to 

build capacity for the acquisition of synovial and kidney biopsies in the United States, and 

standardization of sample processing protocols across multiple research sites. In addition, the 

program is making its data available to the broader research community to foster additional 

research on autoimmune diseases and enhance the return on investment in the program. 

During the first phase of the program, investigators compared cells taken from the tissues of 

rheumatoid arthritis or lupus patients to cells from unaffected individuals with the goal of 

identifying changes in cells and biological pathways that occur in disease, but not in health. 

Results from phase I studies of rheumatoid arthritis revealed that certain subpopulations of 

immune cells and fibroblasts are increased in individuals with rheumatoid arthritis compared to 

controls. Phase I studies of lupus uncovered subsets of white blood cells that are active in the 3

disease and identified specific proteins that could be explored as therapeutic targets. Other lupus 4

phase I studies revealed differences between keratinocytes and kidney tubular cells of individuals 

36 
 

 

 

 

with lupus nephritis versus healthy controls in the expression of genes that respond to type I 

interferon proteins.5, 6 

In the second phase, the network is exploring differences at the molecular level among patients 

with the same disease to determine why disease course and response to therapy can vary so 

widely among patients with the same disease. Understanding this variation could pave the way 

for precision medicine—the ability to tailor treatments to individuals. Early indications from the 

lupus studies suggest that differences in so-called “interferon signatures” between individuals 

with lupus can help predict whether a particular patient is likely to respond to therapy.6 

Additional phase II studies are expected to provide further insights into differences that could be 

used to personalize therapy for rheumatoid arthritis and lupus. 

For further information see: 

1 The Accelerating Medicines Partnership website. 

2 The NIAMS website for the AMP Rheumatoid Arthritis/ Systemic Lupus Erythematosus 

Program. 3 Zhang F, et al. Nat Immunol. 2019. PMID 31061532. 4

Arazi A, et al. Nat Immunol. 2019. PMID 31209404. 5 Der E, et al. JCI Insight. 2017. PMID 28469080. 6 Der E, et al. Nat Immunol. 2019. PMID 31110316. 

Broad areas of potential research directions include: 

• Building on the successful treatment of adult rheumatoid arthritis with disease-modifying 

anti-rheumatic drugs, particularly early interventions to prevent progression to severe 

disease and tissue damage, to advance the development of therapies for other arthritic and 

rheumatic diseases of children and adults (e.g., lupus, scleroderma, ankylosing 

spondylitis, other spondyloarthropathies); 

• Creating therapeutic strategies to target immune dysregulation in rheumatic and 

autoinflammatory diseases; 

• Developing approaches to prevent autoimmune diseases and promote immune tolerance 

(e.g., by screening for factors that promote desired immunological outcomes in B cells); 

• Fostering pharmacogenetic and pharmacogenomics research to investigate the molecular 

basis of individual therapeutic response using robust genetic and genomic approaches; 

• Exploring tissue-remodeling pathways involved in end-organ damage to better 

understand pathophysiology and etiology of rheumatic diseases and to identify new 

therapeutic approaches; 

• Improving patient stratification to enhance translational research studies including studies 

of remission, disease prevention and progression, and treatment response; and 

37 
 

 

• Exploring gene- and cell-based therapies to treat or prevent disease and combinations of 

drugs/biologics in treating rheumatic and autoinflammatory diseases. 

Biomarkers 

The goal of biomarker research is to use modern approaches to discover, validate, and qualify 

biomarkers for use in disease diagnosis, prognosis, and evaluation of therapies. In general, 

molecular/cellular biomarkers are measured in blood, body fluids, or tissues. For many disorders, 

a panel of biomarkers rather than a single biomarker may provide the most clinically useful 

information. 

Broad areas of potential research directions include: 

• Identifying peripheral blood and organ-specific biomarkers that correlate with activation 

of specific pathways in tissues and can be used to predict disease risk preclinically and/or 

to monitor onset and disease progression; 

• Applying new technologies including metabolomics to identify novel specific predictive 

biomarkers; 

• Developing innovative disease monitoring strategies such as in-home testing; 

• Accelerating the transition of promising biomarkers from bench to clinic using state-ofthe-art statistical, analytical, and computational methods; 

• Defining and testing algorithms that integrate different sets of biomarker data within an 

appropriate population (e.g., genetic, imaging, serologic, patient-reported) with sufficient 

power to facilitate personalized clinical decision making regarding diagnostic tests, 

treatments, and prevention strategies; and 

• Developing validated and standardized outcome measures to enable better assessment of 

biomarkers and success of interventions across diverse populations. 

Imaging 

Imaging early or late changes in disease in target organs is increasingly important for 

characterizing disease status and determining responses to therapies. Advanced imaging 

technologies are providing insights into anatomic changes in disease states. For example, 

magnetic resonance imaging (MRI) has been used to detect structural pathology in rheumatoid 

arthritis and ankylosing spondylitis. 

Broad areas of potential research directions include: 

• Optimizing detection and quantitative measurements of structural pathology and 

inflammatory activity with MRI, ultrasound, optical tomography, or positron emission 

38 
 

 

tomography (PET) for assessing, classifying, treating, and monitoring therapeutic 

responses in systemic rheumatic and autoimmune diseases; 

• Developing ultrasound techniques (including 3D) to guide treatment decisions about 

inflammatory joint conditions; 

• Investigating the use of noninvasive imaging technologies in functional studies of disease 

prognosis and progression including intravital microscopy and improved fluorophores to 

gain new insights into cellular interactions and potential mechanisms of disease; 

• Using novel imaging technologies to enable analysis of soft tissues, including heart, 

blood vessels, kidney, and brain, to assess end-organ damage in rheumatic diseases; and 

• Leveraging functional MRI and other evolving and emerging neuroimaging techniques to 

better understand and potentially treat disease-associated features such as pain, fatigue, or 

altered cognition. 

Clinical research 

The complexity of systemic rheumatic and autoimmune diseases, the diverse presentation and 

progression of many of these illnesses across patient populations, and the occurrence of multiple 

comorbid (co-occurring) rheumatic and other complex diseases in the same person, creates 

significant challenges in the diagnosis and management of these conditions. NIAMS supports 

clinical research to advance understanding of these diseases and to develop effective therapies to 

prevent or treat them. 

Clinical studies and trials 

Many rheumatic diseases do not respond adequately to treatment, particularly due to the diverse 

presentation and progression of these illnesses within a patient population, along with complex 

interactions of disease-relevant biological pathways. Therapies that appear to be promising 

through preclinical modeling and testing require clinical testing in defined patient populations, or 

cohorts, as well as creative approaches to assessment of health outcomes. In addition, widely 

available modern imaging technologies (such as ultrasound, optical tomography, and MRI) as 

well as sophisticated wearable devices require testing in clinical trials to evaluate their utility in 

patient care and management. 

39 
 

 

 

Broad areas of potential research directions include: 

• Developing and testing mechanism-based treatments (individual or combinations of 

drugs and biologics), strategies, and/or models of rheumatic diseases that seek to prevent 

onset, induce remission (on or off medication), predict and address disease flare, and 

inform ongoing personalized treatments; 

• Determining whether drugs approved for specific rheumatic conditions can be repurposed 

to treat other rheumatic conditions with similar pathogenic pathways (e.g., drugs 

approved for rheumatoid arthritis in lupus, ankylosing spondylitis, or psoriatic arthritis); 

• Conducting proof-of-concept and bridging studies of approved and available therapeutics 

to address clinically important questions in rheumatic diseases; 

• Establishing the role (qualification) of biomarkers and surrogates to diagnose, predict, or 

monitor disease progression and therapeutic response (efficacy and safety); 

• Employing large systems approaches of disease modeling populated by well-defined 

phenotypes and qualified biomarkers for development of more efficient clinical trial 

designs (by predicting cohort size) and more informed clinical decision making (costeffectiveness, potential toxicity versus prevention, quality-of-life impact over time); 

• Performing studies to better understand treatment and management of rheumatic 

autoimmune disease-related adverse events occurring after treatments such as 

immunotherapy for cancer; 

• Investigating specific treatments and use of imaging approaches (including 3D) for adult 

and pediatric rheumatic diseases; 

• Conducting clinical trials in pediatric populations to determine safety, dosing, and 

efficacy of drugs approved for use in adults with the goal of improving therapeutic 

options for children; 

• Conducting research to improve outcomes for common disorders, such as gout and 

calcium pyrophosphate dihydrate crystal deposition disease, that are expected to worsen 

due to several factors affecting the U.S. and global populations (e.g., aging, obesity); 

• Studying the pharmacogenomics of responders and nonresponders to pharmacologic and 

biological interventions in rheumatic diseases to direct therapies to appropriate subsets of 

patients; 

• Developing, validating, and disseminating clinical outcome measures for rheumatic 

autoimmune diseases in adults and children, including outcomes needed to advance 

personalized therapies and novel trial designs; 

• Conducting clinical studies to determine benefits of treat-to-target-trials as compared to 

current strategies that focus on the level of disease activity or symptoms; 

• Conducting clinical trials related to cause, prevention (e.g., vaccination to prevent herpes 

zoster), and treatment of system-specific pain; 

40 
 

 

 

• Examining the effects of adding adjunctive treatments for comorbidities (e.g., pain, 

fatigue, depression) to standard therapy for rheumatic diseases in individuals with 

comorbidities; 

• Developing functional outcome measures, including pain-related PROs, and biomarkers 

for chronic pain that could be used to assess the effects of treatments to alleviate pain on 

short- and long-term functional status; 

• Using comparative effectiveness approaches to evaluate the effectiveness and safety of 

therapies and using combination-therapy approaches for treating rheumatic disease (e.g., 

compare the effectiveness of traditional therapies to biologic disease-modifying antirheumatic drugs in rheumatoid arthritis); 

• Exploring alternative clinical trial designs and statistical approaches for rare rheumatic 

diseases; and 

• Expanding the involvement of clinical practice physicians and other health care providers 

in community settings in large-scale trials. 

Epidemiology and health services research 

The incidence, morbidity, and mortality of rheumatic diseases are important foci for 

epidemiological research, particularly for studying complex, systemic autoimmune diseases and 

comorbidities. Health services delivery requirements for people with rheumatic diseases is an 

important example of how illnesses with low mortality can still exert significant physical and 

quality-of-life effects. 

Broad areas of potential research directions include: 

• Defining and testing preclinical strategies to understand disease pathways in humans to 

facilitate individualized screening and risk detection to prevent or treat early disease; 

• Combining analysis of the natural history of disease with population-based 

epidemiological studies to determine the prevalence of diseases and associated 

comorbidities (e.g., cardiovascular disease); 

• Studying the long-term outcomes of chronic, systemic rheumatic, autoimmune and 

autoinflammatory diseases that begin in childhood; 

• Conducting research on ways to improve access to specialized care (especially for 

historically disadvantaged populations) and to facilitate patient-health care system 

interactions for improved disease outcomes; 

• Researching the effects of patient-health care system interactions in disease outcomes; 

• Conducting research on environmental exposures, including the microbiome, that may 

contribute to rheumatic diseases, including systems epidemiology research to investigate 

the exposome, and integrate it with genomic, proteomic, and other “omics” datasets; 

41 
 

 

• Focusing prevention studies on risk factor identification and reduction strategies, and 

conducting early-intervention trials to prevent onset or progression of disease or tissue 

injury; 

• Exploring interactions between rheumatic diseases and common comorbid conditions, 

such as atherosclerosis, obesity, and metabolic syndrome, to design effective risk 

management strategies, appropriate monitoring, and evidence-based early interventions; 

• Investigating the safe use of therapies, especially biologics, in pregnant women and 

infants; and 

• Applying computational tools and mobile health technologies to epidemiological studies 

of autoimmune diseases. 

Behavioral and biopsychosocial research 

There is a need to better understand social determinants of health (defined as the conditions in 

which people are born, grow, work, live, and age), and the wider set of forces and systems 

shaping the conditions of daily life, especially for health disparities. Behavioral and social 

science research is contributing important epidemiologic information and approaches to 

managing mental health and distressing symptoms of these disorders. Interdisciplinary 

investigations that integrate behavioral, social, and biomedical sciences will likely enhance 

treatment and management of patients with rheumatic diseases, reduce disability, and may shed 

light on complex mechanisms involved in disease processes. 

Behavioral 

Broad areas of potential research directions include: 

• Exploring cognition and cognitive dysfunction in rheumatic diseases, including use of 

brain imaging and assessment of relationships among cognition, mood disturbance, and 

disease activity; 

• Generating theoretical models for the potential influence of stress on disease course and 

presentation (e.g., symptom flares) to evaluate the influence of stress management 

techniques and interventions on illness and to elucidate potential mechanisms of stressillness interactions; 

• Applying new approaches to study fatigue (e.g., PROMIS measures) in rheumatic 

diseases, focusing on epidemiological issues, potential mechanisms, prevention, and 

treatment; 

• Exploring multidisciplinary approaches to investigate sleep disturbances and their 

relationships to disease processes, symptoms, and disability in rheumatic diseases; and 

• Using mobile health technologies (e.g., smart phones) and web-based technologies to 

facilitate research on the role of behavioral factors in rheumatic diseases, such as efficient 

42 
 

 

 

collection of patient-generated data between clinic/study visits (e.g., telehealth), 

implementation of digital interventions, and the use of wearables (e.g., smart watches) 

involving a broad range of ethnic and social groups. 

Psychosocial 

Broad areas of potential research directions include: 

• Studying the interaction of biological influences with social and/or behavioral factors as 

they relate to disease onset, progression, and outcomes of rheumatic diseases; 

• Defining effects of systemic and societal influences on disease progression, treatment 

response, quality of life, and other patient-reported outcomes in rheumatic diseases; 

• Studying variability in patient outcomes, symptom perception and management, and 

interactions with health care systems that may be affected by behavior, gender, ethnicity, 

family environment, prior trauma, education, or a combination of these factors; 

• Exploring behavioral factors that influence patient interactions with providers and how 

this experience affects treatment response and long-term outcomes; 

• Understanding the impact of stress and adverse childhood experiences on disease activity, 

including flares and overall health, to inform strategies for disease management, 

treatment, and prevention; 

• Examining psychosocial prevention and intervention modalities proven effective in other 

disorders (e.g., diabetes, AIDS) to promote healthy behaviors and management strategies 

for people/patients with rheumatic diseases; and 

• Addressing cross-cultural validation of outcomes instruments and other issues in pediatric 

rheumatology, including pain, psychosocial adjustment, physical functioning, and 

transition from pediatric to adult care. 

Novel therapies 

Broad areas of potential research directions include: 

• Investigating use of integrative, complementary, and behavioral interventions (e.g., 

biofeedback, relaxation, physical therapy, mind-body interactions, cognitive behavioral 

therapy, exercise, diet, dietary supplements) to manage pain and fatigue symptoms 

associated with rheumatic diseases; 

• Integrating patient-reported outcomes and clinical measures to support personalized 

medical decision making and improve quality of life for people with chronic conditions; 

• Investigating placebo responses to pain and treatment and the impact of catastrophizing 

and individual pain experiences on disease management and treatment response; and 

43 
• Investigating the role of nonpharmacological treatments and combined individual, group, 

and technology-based interventions and evidence-based community programs for selfmanagement and improvement of health-related behaviors. 

44 
 

 

 

Advancing and Accelerating Skin Biology and Diseases Research 

NIAMS Skin Biology and Diseases programs fund basic, translational, and clinical research in 

skin, including both common and rare skin diseases. These programs include investigations of 

the basic molecular, cellular, and developmental biology of skin, as well as studies of skin as an 

immune, sensory, endocrine, and metabolic organ. Research on wound healing, autoimmunity, 

inflammation, heritable diseases, and birth defects is also included, with a focus on translating 

fundamental research findings into novel diagnostic tools, effective therapeutics, and efficient, 

cost-saving disease management. 

Understanding skin biology in the context of whole-body physiology is a new horizon. Skin is an 

integral part of the human body, and skin function and skin diseases are influenced by internal 

and external environments. Increasing evidence suggests that skin homeostasis is modulated by 

the immune, nervous, and endocrine systems, as well as by circadian rhythms and resident 

microbial flora. Studying interactions between skin and other organs is increasingly important 

for advancing knowledge of skin health and disease and thus calls for multidisciplinary 

collaborations to invigorate and enrich the skin research field. 

Transdisciplinary basic studies 

Advances in basic research on skin biology have been the foundation for improving skin health 

over the past century. Basic research will continue to be the driving force for innovation in 

combating diseases affecting skin as a whole or in specific regions of the body, as well as skin 

appendages such as hair and nails. 

Skin molecular and cell biology 

Understanding skin biology at the cellular and molecular levels is the foundation for elucidating 

normal and disease processes at the tissue level. These types of studies are intimately connected 

to the state-of-the-art technology and methodology used to understand DNA structure, chromatin 

organization, gene regulation, inter- and intracellular communication, and cellular control 

mechanisms and behavior in living tissues. 

Broad areas of potential research directions include: 

• Investigating chromatin structure and epigenetic mechanisms (e.g., noncoding RNA); 

• Studying the 3D genome; 

• Using 3D genomic data and other epigenetic data to determine how genetic variants in 

noncoding regions of the genome contribute to skin diseases; 

45 
 

 

 

• Studying transcriptional, co-transcriptional, and post-transcriptional regulatory 

mechanisms; 

• Researching skin-specific cell biological mechanisms, for example, 

proliferation/differentiation, movement, sensing, intracellular transportation, secretion, 

signal networks, and intercellular communication; 

• Identifying and characterizing novel populations of cells (single or small number) in 

human skin to improve understanding of cellular composition and heterogeneity; 

• Investigating interactions between the skin and other organ systems, as well as systemic 

effects of perturbations in skin homeostasis; and 

• Capitalizing on the accessibility of skin to pursue unique opportunities to develop realtime, in vivo, noninvasive methods for observation and intervention. 

Stem cells 

Skin structure and function are developed and maintained by a variety of stem cells (e.g., 

keratinocyte stem cells, hair follicle stem cells, melanocyte stem cells, sebaceous gland stem 

cells, mesenchymal stem cells). Understanding skin stem cells is a key research area. 

Broad areas of potential research directions include: 

• Defining stem cell populations in skin, determining the regulatory mechanisms that 

control self-renewal and lineage commitment, and elucidating the role of these cells in 

skin development, homeostasis, and diseases; 

• Identifying the location, components, and properties of stem cell niches, and how these 

niches maintain stem cell populations; 

• Defining stem cell developmental potential (pluripotency), progeny heterogeneity, and 

the possibility of interlineage conversion via dedifferentiation; 

• Mapping cellular lineages in skin and determining how different cell types/subtypes 

interact with each other and identifying the importance of these interactions in 

development, homeostasis, and disease; and 

• Exploring the use of induced pluripotent stem (iPS) cell technology as a tool of research 

and a modality of therapy. 

Developmental biology 

Skin is an organ containing multiple tissue types and appendages. How this complex structure 

arises from a simple epithelial layer during embryonic development has fascinated researchers 

for more than a century. Understanding skin developmental biology has contributed to recent 

advances in promoting skin regeneration and wound healing and in combating diseases. 

46 
 

 

 

 

 

 

 

Broad areas of potential research directions include: 

• Understanding the developmental mechanisms of vertebrate skin; 

• Defining specific genes, signals, and regulatory pathways in the development of skin and 

its appendages that shape skin as an organ; and 

• Illuminating interactions among components of dermis and epidermis during 

development. 

Skin as a barrier 

The primary function of skin is to provide a physical barrier that is flexible, resilient to 

mechanical force, properly sealed, and capable of blocking ultraviolet radiation, with regional 

specializations to accommodate movement, pressure, and friction. The skin barrier is also 

biological, keeping microbial flora at appropriate levels and repelling their infiltration. Defects 

in skin barrier structure and function are a major cause of diseases. 

Keratinocytes (epidermis) 

Keratinocytes are the principal cells that form the body’s outer physical barrier. They 

also contribute to other functions of skin (e.g., immune and sensory). 

Broad areas of potential research directions include: 

• Delineating the developmental pathways of keratinocytes to improve understanding of 

skin diseases, identify potential therapeutic targets, and enable researchers to convert iPS 

cells into differentiated keratinocytes; 

• Investigating the structures and mechanisms that maintain structural integrity of 

epidermis or, when defective, contribute to the underlying pathogenesis of pemphigus, 

pachyonychia congenita, forms of epidermolysis bullosa, and other diseases; 

• Studying changes in the skin permeability barrier caused by circadian rhythms, aging, 

and disease; 

• Identifying targets for therapies to restore normal barrier function in disease and 

conditions such as premature birth; 

• Determining how the skin barrier affects topical therapy and transdermal delivery for 

topical and systemic agents; and 

• Investigating the role of keratinocytes in skin immune and sensory functions. 

47 
 

 

 

Skin photobiology and melanocytes 

Electromagnetic radiation, visible or invisible, has many effects on normal and pathological 

skin physiology. A primary shield of this radiation is created by melanocytes, cells that possess 

unique properties that protect vital stem cells and subcutaneous tissues through the production 

and transfer of melanin to keratinocytes. Pathological conditions affecting melanocytes can lead 

to hyper and hypopigmentation of skin that can significantly affect an individual’s quality of 

life. 

Broad areas of potential research directions include: 

• Studying effects of electromagnetic radiation on skin biology (e.g., activation of melanin 

synthesis, vitamin D synthesis, and immunosuppression); 

• Determining melanocyte stem cell and lineage development; 

• Investigating melanocyte cell biology and population heterogeneity; 

• Studying melanosomes and melanin synthesis and transfer pathways; 

• Exploring the role of melanocytes in overall skin photobiology (e.g., their interactions 

with other cell types); and 

• Identifying molecular and genetic differences between preneoplastic and senescent nevi. 

Skin fibroblasts and extracellular matrix 

Basement membrane and dermis provide much of the structural support and mechanical strength 

of the skin barrier. Scientists are just now appreciating the role of extracellular matrix (ECM) in 

regulating cytokine activity and cellular behavior. A major focus of research in this area is 

determining how fibrosis develops. Another important area is understanding inherited defects in 

ECM proteins, that is, heritable connective tissue disorders (see also Genetics, below, for more 

information). 

Broad areas of potential research directions include: 

• Investigating the biology of normal fibroblasts and their transition (e.g., 

transdifferentiation to myofibroblasts) during normal and diseased physiology; 

• Defining dermal fibroblast diversity in different body sites to understand cell types 

involved in skin diseases that preferentially affect distinct parts of the body (in 

conjunction with skin innervation patterns; see also Skin as a Sensory and Endocrine 

Organ); 

• Uncovering interactions between epidermal and dermal components and the role of these 

interactions in the development of diseases; 

48 
 

 

 

 

 

 

• Studying mechanisms that control the normal assembly, interactions, and function of 

molecular components of the ECM; 

• Studying regulatory function of the ECM and ECM-cell interaction; and 

• Understanding mechanisms of ECM-related diseases. 

Skin vasculature and adipose tissue 

The cutaneous vascular plexus of the dermis/hypodermis is a dynamic, environmentally 

responsive network of blood vessels that provides nutrients, acts as a conduit for the immune 

system, and is involved in thermoregulation and wound healing. The skin is also home to an 

elaborate network of lymphatic vessels that parallels the major blood vascular plexuses and 

enables clearance of fluids, macromolecules, cells, and foreign material from the dermis. 

Subcutaneous adipose tissue has been understudied, and recent advances suggest that in addition 

to thermo-insulation, its functions also include regulation of wound healing, fibrosis, hair 

cycling, and the innate immune response to bacterial infection. 

Broad areas of potential research directions include: 

• Expanding understanding of mechanisms controlling angiogenesis, lymphangiogenesis, 

and structure and function of blood/lymphatic vessels in normal skin development; 

• Investigating and understanding the cellular/molecular biology and genetics of skin 

vasculature that contribute to cutaneous vascular malformations or affect angiogenesis in 

chronic wounds and in inflammatory and fibrotic diseases; and understanding the cause 

of skin vasculature birth defects (e.g., hemangioma and port wine stain) and developing 

effective therapies; 

• Researching the role of adipose tissue in skin homeostasis and whole-body physiology; 

and 

• Studying the role of adipocytes in skin repair, regeneration, and fibrotic diseases. 

Breach of the barrier 

Barrier defects and wounds can lead to a variety of skin diseases. Barrier leakage can cause 

excessive loss of water and other small molecules or increased infiltration of environmental 

substances including microorganisms that lead to skin immune reactions. More severe disruption 

of the skin barrier triggers a wound-healing response, a complex process shaped during evolution 

to ensure rapid restoration of tissue integrity. A large repertoire of cell types performs multiple 

functions during this process: covering the wound bed, fighting microbial infection, and 

rebuilding tissue architecture, an inherently multifaceted process. 

49 
 

 

 

 

 

Broad areas of potential research directions include: 

• Studying the molecular basis of barrier leakages and their consequences; 

• Assessing the relationship between barrier defects and skin immune reactivity; 

• Understanding how wound healing begins and ends; 

• Defining minimal injury at the molecular level that triggers wound healing; 

• Understanding how injury is detected; 

• Studying basic mechanisms of wound healing, such as stem cell activation, cell-identity 

change, cell migration, differentiation, ECM remodeling, angiogenesis, and inflammation 

control; 

• Investigating the role of systemic/mesenchymal stem cells (e.g., bone marrow derived) in 

skin wound healing; 

• Understanding interactions of multiple systems, factors, and pathways such as 

interactions among components of epithelia, endothelia, connective tissue, and 

mesenchymal, immune, and inflammatory cells; 

• Researching the milieu of slow-healing and chronic wounds to identify factors that impair 

healing; 

• Defining molecular and genetic mechanisms that contribute to aberrant/exuberant wound 

healing, fibrosis, or scar/keloid formation; and 

• Exploring the role of ECM remodeling in normal wound healing and diseases (e.g., 

chronic wounds, keloids), as well as effects of ectopic mineralization. 

Skin as an immune organ 

Skin is not only a major physical barrier but also a complex neuroimmune organ densely coated 

by microbial communities and populated by keratinocytes, neurons, hair follicles, and resident 

immunocytes. In combination, these cells provide a robust immunological barrier to potential 

insults. In response to invading pathogens, groups of cells—including microbial commensals, 

keratinocytes, and immunocytes—together neutralize invaders and subsequently restore skin 

homeostasis. Failure to restore skin homeostasis may lead to microbial dysbiosis and deregulated 

cutaneous innate and/or adaptive immunity, resulting in inflammatory and/or autoimmune skin 

diseases. 

Immunobiology of the skin 

Keratinocytes screen their microenvironment continuously and respond rapidly to signals by 

expressing pro-inflammatory cytokines, chemokines, and antimicrobial peptides (AMPs). In 

addition, keratinocytes can initiate adaptive immunity by presenting foreign antigens to resident 

skin memory T cells and effector T cells. Multiple other types of immunocytes, such as 

Langerhans cells, dermal dendritic cells, macrophages, monocytes, innate lymphoid cells, and 

50 
 

others also screen the external microenvironment, epidermis, and/or dermis. Importantly, 

microbial commensals help the skin-based immune system mature and release factors such as 

AMPs that antagonize pathogen invaders. Skin is also innervated, and the functions of 

immunocytes, keratinocytes, and neurons are linked. Findings focused on the regulatory role of 

microbial commensals, keratinocytes, and immunocytes—and their expressed factors, such as 

cytokines, chemokines, microbial and keratinocyte AMPs, and neuropeptides—have opened new 

avenues to understanding the immunobiology of healthy and diseased skin. 

Broad areas of potential research directions include: 

• Studying skin as an active immune organ, focusing on keratinocytes and innate and 

adaptive immunocytes, as well as their receptors and soluble factors (using single-cell 

RNA sequencing, CyTOF, and other new technologies); 

• Developing in vivo and in vitro 3D skin models, including skin on a chip, that include 

immune components, to define key regulatory signaling pathways activated in human 

keratinocytes and/or immunocytes; 

• Discovering new mechanisms by which commensals, neurons, keratinocytes, and 

immunocytes interact and synergize; 

• Defining bidirectional molecular signals that skin microbial communities use to 

communicate with each other and with the cutaneous immune system; 

• Determining how changes in the skin barrier affect the ecology of the microbial 

communities on the skin’s surface and their access to the dermal compartment; 

• Identifying mechanisms by which resident microbiota of the gut, lung, oral cavity, and 

other mucosa affect skin’s resident microbial communities; 

• Defining the role of glycobiology in skin immune responses; 

• Understanding the molecular basis by which the cutaneous immune system and systemic 

immune system influence one another; 

• Developing models to define the molecular basis by which the cutaneous immune 

system, the endocrine system, and the nervous system communicate in healthy and 

diseased skin; 

• Developing intravital imaging and nanotechnology to study skin structure, cell migration, 

cell interaction, and intracellular trafficking in live skin; 

• Analyzing influences of subcutaneous adipocytes and corresponding lipid metabolism in 

the control of skin immune functions; and 

• Defining the role of the skin immune system in the initiation, development, and 

surveillance of skin cancer. 

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Inflammatory and immune skin diseases 

The easy accessibility of skin facilitates molecular and cellular analyses of lesions and enables a 

systems biology approach to studying inflammatory and autoimmune skin diseases. These types 

of studies identify functional signatures of these diseases, for example, differentially regulated 

genomics, epigenomics, transcriptomics, proteomics, and metabolomics, and changes in 

activated cellular subsets, antibody and receptor repertoires, signal transduction pathways, and 

the microbiome. 

Genetic and epigenetic studies of skin immune diseases 

Additional research is needed to improve understanding of cellular and molecular mechanisms 

that contribute to complex skin disease pathogenesis. Artificial intelligence and computational 

models that integrate information obtained from high-throughput proteomics, transcriptomics, 

genome-wide association studies (GWAS), deep genome-wide sequencing studies, the 

Encyclopedia of DNA Elements (ENCODE) project, 3D chromatin structure and epigenetic 

markers data, and functional genomic studies will reveal novel mechanism by which genomic 

and proteomic alterations result in clinical manifestations of skin immune diseases. 

Broad areas of potential research directions include: 

• Using genetic and functional genomics approaches to investigate pathogenic mechanisms 

and skin disease progression; and 

• Studying roles of gene-environment interactions, epigenetics, noncoding regulatory 

DNA, chromatin interactions, and other modifiers of gene expression (e.g., microRNAs, 

lncRNAs) in disease pathogenesis. 

Pathogenesis studies 

More research is needed to discover innate and/or adaptive cellular and molecular mechanisms 

that trigger and control pediatric and adult inflammatory and autoimmune skin conditions such 

as hidradenitis suppurativa, Steven-Johnson-TEN, pemphigus, pemphigoid, psoriasis, atopic 

dermatitis, ichthyosis vulgaris, alopecia areata, cicatricial alopecia, vitiligo, acne, rosacea, 

immune-mediated itch, and others, and to understand comorbidities associated with them. 

Activities described in the box “Understanding Co-occurring Conditions in Psoriasis” are 

examples of research to address comorbid conditions associated with psoriasis. 

52 
 

Understanding Co-occurring Conditions in Psoriasis 

Certain chronic diseases seem to occur together. For example, psoriasis is associated with an 

increased risk of developing conditions such as cardiovascular disease, diabetes, depression, and 

psoriatic arthritis. Managing the care of patients with multiple simultaneous health issues, often 

referred to as comorbidities, is challenging. In addition, patients with multiple chronic conditions 

may have worse health outcomes and quality of life than other patients. Recognizing the 

importance of addressing co-occurring conditions, NIAMS supports research to understand why 

such conditions develop, identify patients at highest risk for them, and determine how best to 

treat their conditions. 

As part of its investment in psoriasis research, NIAMS supports a varied portfolio of efforts 

related to co-occurring conditions. A 2017 NIAMS roundtable brought together researchers in 

dermatology and rheumatology to discuss research needs in psoriatic arthritis, a form of joint 

inflammation that can occur in people with psoriasis.1 A NIAMS-funded translational research 

center is using cutting-edge technologies and clinical and laboratory data from patients to help 

predict which patients are most likely to develop comorbidities and to identify drugs that could 

be repurposed to treat them.2 

Several NIAMS-funded studies have provided information that could improve treatment and 

management of psoriasis comorbidities. One such project, which examined the risk of type 2 

diabetes in people with psoriasis, suggests a link between psoriasis severity and the development 

of diabetes.3

 The results underscore the importance of diabetes prevention in psoriasis, especially 

for those with severe disease. Another study showed that individuals with psoriasis, particularly 

those prescribed a systemic therapy, that is, a drug that spreads throughout the body, are at 

increased risk for developing liver disease. This suggests that patients on systemic therapy 

should minimize exposures, for example, to certain medications, that may damage the liver.4 

Other work supported by NIAMS tested whether the anti-inflammatory drug adalimumab 

mitigates the increased cardiovascular risk seen in patients with severe psoriasis.5 Although the 

drug was not effective at reducing cardiovascular risk factors, the results provide important new 

information for clinicians as they decide the best course of treatment for their patients. 

For further information see: 

1 Summary of the 2017 Roundtable. 2 The Center of Research Translation Project Information. 3 Wan MT, et al. J Am Dermatol. 2017. PMID: 29128465. 4 Ogdie A, et al. J Invest Dermatol. 2018. PMID: 29104161. 5 Metha NN, et al. Circ Cardiovasc Imaging. 2018. PMID: 29776990. 

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Broad areas of potential research directions include: 

• Using artificial intelligence and machine learning to define personalized medicine 

profiles through integration of electronic medical records and patients’ cellular and 

molecular signatures; 

• Including diverse populations in the creation of artificial intelligence systems to improve 

understanding of disease manifestations in different skin types; 

• Investigating unique or shared cellular and molecular mechanisms involved in the onset, 

development, and progression of immune-mediated skin diseases; 

• Investigating CD-1-based glycolipid skin immune responses and their role in 

inflammatory skin diseases; 

• Using single-cell RNA sequencing to study cells isolated from skin biopsies of human 

inflammatory skin disorders; 

• Exploring the mechanisms by which cytokines, chemokines, or autoantibodies cause 

symptoms in skin diseases to inform development of drug therapies; 

• Studying the role of the skin and gut microbiomes as potential triggers and regulators for 

autoimmune and inflammatory diseases of skin; 

• Investigating innate and adaptive signaling pathways that contribute to skin disease 

symptoms and comorbidities (co-occurring conditions) such as cardiovascular disease, 

metabolic syndrome, and diabetes; 

• Using epidemiology “big data” and analytical methods to link skin diseases with systemic 

comorbid (co-occurring) conditions; 

• Characterizing altered lipid metabolomics and glycolysis pathways leading to 

inflammatory and autoimmune skin diseases; and 

• Understanding the role of T cells, for example, the role of resident memory T cells in skin 

diseases including mechanisms of treatment failure and longevity of treatment effects. 

Skin as a sensory and endocrine organ 

Skin is the body’s largest interface with its immediate external environment and it is exposed to 

numerous physical, chemical, and biological stimuli. Thus, over time, skin has evolved into a 

sensory organ and an extension of the body’s nervous and immune systems that interacts with 

the external environment. Skin is also an endocrine organ, known as a site of hormone 

synthesis, and capable of communicating with the rest of the body via multiple endocrine 

pathways. 

Research needs and opportunities related to itch were discussed in greater detail at a 2010 

NIAMS roundtable discussion and remain relevant to this Strategic Plan. 

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Broad areas of potential research directions include: 

• Studying skin innervation; 

• Defining sensory functions of resident skin cells (e.g., keratinocytes, Merkel cells, 

components of hair follicle); 

• Studying mechanisms of itch and pain and defining their mediators in skin under normal 

and pathological conditions; 

• Examining mechanisms of touch and temperature sensation; 

• Investigating interactions among skin sensations, that is, itch, pain, touch, and 

temperature; 

• Developing therapeutic methods to control itch and pain in disease conditions; 

• Investigating the role of skin innervation in normal tissue and in pathological conditions 

such as inflammation and chronic wounds; and 

• Understanding skin’s endocrine function. 

Skin appendages 

Skin appendages, for example, hair, nail, sebaceous glands, and sweat glands, provide many of 

the auxiliary functions of skin. Compared to the epidermis, these epithelia-derived miniorgans/tissues are understudied. One exception is hair/the hair follicle—a powerful model system 

for understanding tissue/organ development and regeneration. 

Broad areas of potential research directions include: 

• Studying development and maintenance of skin appendages; 

• Identifying potential stem cells and their niches; 

• Understanding function and regulation of stem cells in normal skin and in pathological 

conditions; 

• Investigating the etiology of diseases related to skin appendages; and 

• Understanding the regenerative potential and conditions of skin appendages. 

Genetics 

Many, if not all, aspects of skin function are known to be affected by genetic mutations, 

producing a spectrum of clinical manifestations ranging from minor, cosmetic, and irritant 

(deteriorating quality of life) to fatal. Genetic factors that affect skin conditions can be 

monogenic, polygenic, or mosaic, including sequence variations in protein-coding DNA and in 

noncoding regulatory regions that operate through genetic and epigenetic mechanisms. A better 

understanding of these genetic and epigenetic factors, as well as how the variants and mutations 

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contribute to disease phenotype, is essential to develop effective therapies. A large repertoire of 

therapeutic modalities is employed to combat heritable skin diseases. 

Broad areas of potential research directions include: 

• Using high-throughput genomic and other technologies (e.g., GWAS, whole and exome 

sequencing) to discover new genetic underpinnings of skin diseases; 

• Determining how genetic variants and mutations lead to disease phenotype; 

• Defining modifier genes and the effect of genetic background on phenotype 

heterogeneity, disease risk, and severity; 

• Identifying and characterizing biochemical and cellular networks affected by mutations 

underlying skin diseases; 

• Understanding mechanisms of spontaneous reversion of disease phenotype in some 

genetic diseases and exploring therapeutic potential of these processes; 

• Applying high-throughput genomic and epigenomic technologies, combined with 

computational methodologies, to elucidate regulatory networks involved in normal skin 

biology and in disease states; 

• Deploying deep genomic sequencing technologies to identify postzygotic somatic 

mutations that lead to pathological changes; 

• Applying single-cell genomic and epigenomic analyses to better understand cell 

heterogeneity in normal and diseased skin and to trace cell lineages during skin 

development and homeostasis; and 

• Developing technologies that allow single-cell analyses to be performed on cells isolated 

from human skin biopsies. 

Regenerative medicine 

Regeneration mimics the embryonic process that shapes original tissue; therefore, it heals injury 

without the scarring and functional deficits associated with repair, which relies on the use of 

substitute, or “makeshift,” material to close a wound rapidly. Because only limited tissue 

regeneration occurs in humans, treatment of large-area acute skin wounds, such as extensive 

burns and trauma, involves both regeneration and repair and a key challenge is how to restore 

tissue function after a wound is closed. Regenerative medicine in skin involves research on 

developmental processes, tissue neogenesis, stem cells, the skin microenvironment, and 

engineering approaches to create temporary tissue substitutes or modify wounds for improved 

healing and functional restoration. 

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Skin embryonic development 

The concept and practice of regenerative medicine are firmly rooted in developmental biology. 

Knowledge of developmental biology principles related to skin provides important insights 

into tissue regeneration. Studies of hair follicle neogenesis have revealed that adult skin may 

possess more regenerative capacity than previously thought (see also Developmental biology, 

above). 

Broad areas of potential research directions include: 

• Applying principles of skin and skin-appendage development to regeneration of normal 

skin following injury; and 

• Applying knowledge of skin and skin-appendage development to engineering of 

replacement skin in the laboratory. 

Tissue neogenesis 

Tissue neogenesis is the process of regeneration of lost or damaged tissues or organs in response 

to injury and contrasts with wound healing, which involves closing the injury site and scar 

formation. While non-mammalian vertebrates and some mammals can repair skin without scars, 

human adult skin has very limited regenerative capacity for scar-free repair. The complete 

regeneration of injured or diseased human skin remains the ultimate goal and a major challenge 

of regenerative medicine. 

Broad areas of potential research directions include: 

• Understanding skin’s regenerative potential; 

• Defining conditions that induce or hinder adult neogenesis; 

• Discovering mammalian model systems that can fully regenerate skin and appendages, 

(such as the African spiny mouse); 

• Developing methods for in vivo tracking of exogenous (e.g., transplanted) cells in 

regenerative medicine applications to determine if they play a transient or permanent 

role; and 

• Defining factors that promote exogenous cellular engraftment and investigating 

approaches to maintain transplanted cells’ unique properties in vivo. 

Engineered skin tissues 

3D skin cultures mimic in vivo human skin better than monolayer cultures and provide the 

opportunity for the creation of patient-specific models of disease. These models can be used to 

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study disease pathogenesis and genetics, and to test new therapies. Engineered skin can also be 

used directly as a therapy. 

Broad areas of potential research directions include: 

• Developing a new generation of skin equivalents that can better mimic natural skin

functions (e.g., vasculatures, immune functions, pigmentation, innervations);

• Developing modular skin 3D models that can interact with other organ models to study

integrated human physiology (e.g., as proposed in the NIH Common Fund’s Integrated

Microphysiological Systems initiative);

• Exploring use of iPS cells in engineered skin;

• Investigating use of natural and artificial ECM components as biomaterials that provide

appropriate structural and mechanical properties for generating functional skin; and

• Developing wound coverings for drug/growth factor delivery to promote healing and

regeneration.

Model systems 

In biomedical research and therapeutic development, hypotheses and drugs must be 

evaluated in model systems. These can be living organisms or in silico (computer or 

mathematical) models. 

Animal models 

Genetically modified organisms and many naturally occurring genetic variants are powerful tools 

for skin research. Even so, finding suitable models to address specific questions in skin research 

remains challenging. One recurring issue is whether findings in mouse models can be directly 

translated into humans. Transplantation of human skin to a mouse, or reconstituting the human 

immune system in a mouse, may be useful for investigating some human skin diseases. Some 

complex diseases can be modeled with transgenic mammals, and some polygenic diseases (e.g., 

alopecia areata) have emerged spontaneously in mice and in other large animals. 

Broad areas of potential research directions include: 

• Developing animal models, using state-of-art technology (e.g., CRISPR/Cas, TALENs)

and another approaches (e.g., optogenetics), to study the role of specific genes and

regulatory pathways in the development of skin and its appendages, as well as in skin

homeostasis, regeneration, skin microbiota, and heritable skin diseases and to test new

therapeutic agents;

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• Generating and validating animal models that mimic human skin diseases, including 

grafting of human skin and patient-derived or genetically engineered skin equivalents 

onto mouse skin, to examine molecular and cellular processes in a controlled 

experimental environment; 

• Exploring naturally occurring mammalian models for skin biology, regeneration, and 

diseases (e.g., African spiny mouse or existing inbred mutant mouse strains); 

• Exploring use of simpler organisms (e.g., zebrafish, flies) for modeling skin diseases and 

mutations and for high-throughput genetic screening; 

• Generating animal models to investigate mechanisms of tissue damage by toxic industrial 

chemicals and chemical threat agents and for testing the efficacy of potential 

countermeasures; and 

• Developing specific animal models in conjunction with emerging observation technology 

(e.g., intravital imaging) to enhance the ability to detect, trace, and noninvasively identify 

cellular activity in vivo. 

In vitro cell-based models 

Cultured skin substitutes and other in vitro models of skin are in current use for experimental 

studies and toxicology screening. 

Broad areas of potential research directions include: 

• Developing 3D tissue models of normal human skin and diseases; 

• Using patient-derived iPS cells and other technologies to create disease models to study 

the roles of specific genes and pathways in disease pathogenesis, as well as to test 

therapeutic agents for personalized medicine; 

• Developing efficient, highly reproducible, and scalable protocols to produce 

differentiated skin cell types from iPS cells and methods to validate the identity of the 

resulting cells; 

• Exploring direct reprogramming of adult somatic cells as an alternative strategy to 

generating skin cells for in vitro models and for cell-based therapies; and 

• Developing in vitro models to study host-microbe interactions in skin. 

In silico modeling 

Systems biology is a research approach used to understand the network behavior of biological 

systems, to predict effects of perturbations on a system, or to develop novel ways to modulate a 

system’s behavior. In systems biology modeling, conceptual and mathematical models are 

developed and trained by test data and then used to predict the behavior of real biological 

59 
 

 

 

systems. To facilitate development of a successful systems biology model it is critical to attain 

consensus on standards for collecting and reporting research results. 

Broad areas of potential research directions include: 

• Modeling regulatory networks of genes, proteins, and cells in skin; 

• Encouraging collaboration among biologists and mathematicians to enable the use of 

systems biology approaches to model complex biological processes; 

• Developing disease models (such as virtual patients) to inform clinical trial design and 

clinical practice; and 

• Developing, with artificial intelligence concepts, methods for analyzing and 

understanding large data sets. 

Therapy development 

Knowledge of pathogenic pathways and basic skin biology facilitates development of smallmolecule and biologic therapies (e.g., antibodies) that target specific components of these 

pathways. Such approaches enable effective and systemic treatment with minimal side effects, 

which is desirable for widespread skin lesions. Because of the accessibility of skin, treating 

diseases of skin, hair, and nails—including diseases of the scalp and of skin appendages— 

need not be limited to chemical interventions, since physical methods have also been explored. 

Needs and opportunities related to therapies for pediatric dermatologic disease were 

discussed in 2011 at a NIAMS roundtable, and that discussion remains relevant to this 

Strategic Plan. 

Broad areas of potential research directions include: 

• Translating gene-based discoveries into novel therapeutics; 

• Exploiting drug repurposing for skin therapeutics; 

• Discovering small molecular activators and inhibitors of cellular processes as potential 

therapeutic agents; 

• Studying the pharmacogenomics of responders and nonresponders to pharmacologic and 

biological interventions in skin diseases with the aim of directing therapies to appropriate 

subsets of patients; and 

• Developing interventions that reverse, not merely delay, adverse changes that occur in 

aging skin. 

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Gene and cell-based therapy 

Correcting defective genes may be possible to treat monogenic skin diseases such as 

epidermolysis bullosa (EB) simplex. One possible approach would be to use CRISPR/Cas 

technology in combination with iPS cells, thus addressing the disorder’s root cause. Another 

approach being tested for people with EB is treatment with donor-derived bone marrow stem 

cells. 

Broad areas of potential research directions include: 

• Developing in vivo and ex vivo gene therapies that target single-gene causal defects in 

skin diseases (e.g., various forms of EB); 

• Developing systemic therapies for inherited skin diseases, for example, bone marrow 

transplantation and protein replacement therapy; 

• Investigating the use of small interfering RNAs to treat skin diseases by modulating 

expression of both normal and defective genes; 

• Investigating effective in vivo molecular and cell delivery strategies to heal acute and 

chronic wounds; 

• Developing ex vivo and in vivo gene-correction strategies to treat genetic skin diseases; 

and 

• Exploring the therapeutic potential of various types of stem and progenitor, iPS, and 

embryonic stem cells to generate artificial bioengineered skin replacements for acute and 

chronic wounds and to repair or regenerate other tissues. 

Cutaneous and transcutaneous drug delivery 

The skin barrier makes targeted delivery of small molecules and biological drugs to the 

epidermis and dermis challenging. Conversely, the permeability of this barrier also presents an 

opportunity to consider transdermal delivery strategies to treat systemic diseases. 

Broad areas of potential research directions include: 

• Exploring novel mechanisms of drug delivery to epidermis and dermis; 

• Investigating topical delivery of small molecules and larger biomolecules, such as 

enzymes, monoclonal antibodies, and nucleic acids; and 

• Developing transcutaneous drug delivery strategies for efficient and controlled 

administration of biological therapeutic agents for systemic diseases. 

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Physical therapies 

Several types of physical therapies are used in dermatology practice. Examples include 

phototherapy (e.g., ultraviolet light irradiation) and chemically modified water baths. 

Broad areas of potential research directions include: 

• Discovering, developing, and refining physical methods for diagnosing and treating skin 

diseases. 

Clinical research 

Skin diseases, which frequently compromise quality of life, are not always seen as important 

research targets relative to illnesses with greater mortality and morbidity. However, the impact 

of skin disease on people’s lives is significant. Furthermore, some skin diseases are 

accompanied by systemic effects and comorbidities. 

Clinical trials and outcomes measures 

Clinical trials based on solid preclinical studies are essential for improving the public health. 

Combination therapies, evidence-based comparisons of treatments, and cost-effectiveness are 

critical topics for future research. 

Broad areas of potential research directions include: 

• Identifying clinical biomarkers that predict disease progression and treatment outcomes 

reliably and can be used as surrogate endpoints in clinical trials; 

• Developing and validating new outcomes instruments that better measure disease severity 

and assess disease impact on quality of life for people and their families than current 

instruments; 

• Developing methods to collect patient-reported outcomes and incorporate them in clinical 

studies/trials; 

• Exploring alternative clinical trials designs for rare skin diseases in which cohort sizes 

may be very small; 

• Conducting clinical trials in pediatric populations to determine safety, dosing, and 

efficacy of drugs approved for use in adults with the goal of improving therapeutic 

options for children; 

• Establishing novel disease outcome measures and defining early signatures of disease 

onset and progression; and 

• Exploring safety and efficacy of peptides and non-coding RNA-based therapy. 

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Epidemiology and health services research 

The incidence and morbidity of skin diseases are important subjects for epidemiological 

research. Optimal distribution of health services for skin diseases highlights the relevance of 

treating illnesses with significant physical and quality-of-life effects. 

Broad areas of potential research directions include: 

• Combining analysis of the natural history of disease with population-based 

epidemiological studies to determine disease prevalence and burden on specific 

populations (e.g., underserved); 

• Facilitating observational and epidemiological studies of skin disease comorbidities (cooccurring conditions) and gene-environment interactions that may trigger or exacerbate 

skin diseases; 

• Investigating skin disease comorbidities (co-occurring conditions) as they relate to health 

disparities and therapeutic interventions; 

• Examining the cost-effectiveness and comparative effectiveness of therapies and 

combination-therapy approaches for skin disease treatment and developing the 

infrastructure needed to conduct these studies; 

• Investigating racial and ethnic differences in skin diseases to improve understanding of 

the effect of skin type on diagnosis, treatment response, and other issues; 

• Researching effects of patient-health care system interactions on disease outcomes, 

considering in particular minority and underserved populations; and 

• Developing new methods to collect data (e.g., mobile device, Internet, remote sensing) 

for epidemiological studies. 

Prevention studies 

Prevention studies are critical to promote health through the identification of risk factors for skin 

diseases, disorders, or injuries. They are also important for detecting and preventing progression 

of asymptomatic or early-stage skin conditions. 

Broad areas of potential research directions include: 

• Developing strategies to identify, assess, and reduce disease risk factors; 

• Conducting early intervention trials to prevent onset or progression of disease; and 

• Exploring use of personal communication devices and the Internet as tools for education, 

monitoring, and intervention. 

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Behavioral and biopsychosocial research 

Changing lifestyle and habits can prevent many skin diseases, which provides opportunities for 

behavioral intervention. Furthermore, people with skin diseases are frequently affected by 

psychosocial problems due to social stigma. These factors highlight the role of behavioral and 

biopsychosocial research in combating skin diseases. 

Broad areas of potential research directions include: 

• Using social, commercial, economic, gender, ethnic, and cognitive data to understand 

correlations between behavior and skin diseases; 

• Exploring interventions, including behavioral modification and protective strategies, to 

prevent skin exposure to environmental harm that causes disease and accelerates skin 

aging; 

• Studying mechanisms by which stress affects skin disease progression and wound 

healing, and how stress management affects disease outcomes and treatment response; 

and 

• Investigating management of chronic symptoms, such as itching and pain, as well as 

ways to minimize effects of these symptoms on stress level, sleep, and overall quality of 

life. 

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Advancing and Accelerating Bone Biology and Diseases Research 

The NIAMS Bone Biology and Diseases programs fund a broad spectrum of basic, translational, 

and clinical research on buildup and breakdown of bone. Acquisition and preservation of 

adequate bone mass, as well as maintenance of architectural and material qualities that confer 

bone strength, are crucial for protection against fracture. Osteoporosis, or low bone mass, 

increases risk of fracture with associated morbidity and reduced quality of life. In the United 

States today, more than 53 million people either already have osteoporosis or are at high risk due 

to low bone mass. Because osteoporosis is common among older people—particularly in women 

after menopause—prevention, diagnosis, and treatment of osteoporosis will continue to have 

major public health implications as the U.S. population ages. Healthy People 2030, the Nation’s 

public health agenda, will seek to improve osteoporosis-related outcomes. 

NIAMS supports studies on the control of bone remodeling (bone formation, bone resorption) 

and mineralization, as well as the effects of hormones, growth factors, and cytokines on bone 

cells. The Institute has overseen several large epidemiologic cohorts to characterize the natural 

history of osteoporosis and identify genetic and environmental risk factors that contribute to 

fracture. NIAMS also supports clinical trials to test the effectiveness of interventions to prevent 

fractures associated with osteoporosis and other metabolic bone diseases. In addition, the 

NIAMS Bone Biology and Diseases programs support research on the causes, pathophysiology, 

and treatment of less common bone diseases, such as osteogenesis imperfecta and Paget’s 

disease of bone, as well as a wide range of developmental disorders of the skeleton, many of 

which are genetic. 

Bone biology, physiology, and development 

Molecular and cellular mechanisms in bone 

Bone cells perform key processes in bone remodeling: formation of new bone by osteoblasts and 

resorption or breakdown of old or damaged bone by osteoclasts. In a healthy adult skeleton, 

these processes are balanced through the overall process of bone remodeling. 

Osteocytes, fully mature osteoblasts embedded in mineralized bone, have emerged as a crucial 

population of cells for controlling bone physiology. In addition, cells lining the bone surface play 

an important role in normal and pathologic remodeling. Disproportionate resorption compared to 

formation results in bone loss and can increase risk of fracture. Understanding mechanisms that 

regulate osteoblasts, osteoclasts, and osteocytes and influence bone resorption or bone formation 

may yield new therapeutic targets. Manipulating such processes could also be essential for 

tissue-engineering technologies using bone-forming cells. 

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Broad areas of potential research directions include: 

Bone anabolic mechanisms: osteoblasts and osteocytes 

• Characterizing biochemical pathways that control proliferation of osteoprogenitor 

cells; 

• Defining populations of progenitor cells and early and intermediate cell types during 

differentiation to mature bone-forming osteoblasts and osteocytes, as well as 

mechanisms of transdifferentiation in tissue development and repair; 

• Identifying factors that control progression through cellular lineages; and 

• Elucidating mechanisms that control osteoblast activity and determine the cell’s 

functional lifetime. 

Bone resorption mechanisms: osteoclasts 

• Characterizing biochemical pathways that control differentiation of osteoclasts from 

progenitor cells within the monocyte/macrophage lineage; 

• Defining factors that control maturation of progenitor cells into active multi-nucleated 

osteoclasts; and 

• Identifying biochemical pathways that control osteoclast activity and the functional 

lifetime of cells. 

Bone homeostasis: osteocyte function and action 

• Defining mechanisms that control osteocyte differentiation, including formation of 

osteocyte dendritic processes and the lacunar-canalicular system; and 

• Identifying factors that modulate osteocyte activity in normal and pathophysiological 

conditions, including understanding the effects of diseases and their therapies on bone 

homeostasis. 

Mineralization of bone matrix 

• Defining mechanisms that initiate and control deposition of calcium phosphate 

crystals in the collagen matrix of bone; 

• Elucidating factors that control bone mineralization; 

• Determining the effects of various degrees of mineralization on bone’s structural, 

functional, and mechanical properties; and 

• Identifying the causes of pathological calcification of soft tissues and exploring 

measures to prevent or reverse inappropriate mineralization. 

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Cell-matrix interactions in bone 

• Characterizing specific interactions among osteoblasts, osteoclasts, and components 

of the extracellular matrix of bone that influence cell differentiation or activity; 

• Determining interactions between osteocytes and bone matrix to define the processes 

underlying embedding of cells in mineralized matrix and the formation and 

maintenance of the osteocyte network; and 

• Identifying signaling pathways controlled by cell-matrix interactions in bone. 

Cross-talk between bone cell types 

• Identifying molecules produced in one bone cell type that influence another, 

including those that may be transported in exosomes (e.g., micro-RNAs); 

• Characterizing sites where molecules with effects on other bone cells are produced; 

• Investigating effects of signaling molecules originating in other bone cell types on 

target cells; and 

• Defining the mechanisms coupling bone resorption with bone formation during the 

bone remodeling process. 

Fracture repair 

• Defining the cells and biochemical pathways involved in recruitment of 

osteoprogenitor cells to fracture sites; 

• Describing the processes that lead to callus formation and remodeling of new bone, 

including the roles of loading, inflammation, and vascularization; 

• Identifying and characterizing factors leading to fracture non-unions (i.e., fractures 

that fail to heal); and 

• Defining factors leading to the development of stress fractures and their healing or 

lack thereof. 

Bone response to mechanical loading 

• Characterizing cell populations that mediate the anabolic response of bone to loading; 

• Defining the role of the osteocyte network in mechanosensation and the response to 

loading; 

• Determining the resorptive response of bone to conditions of unloading, such as 

microgravity and disuse; and 

• Elucidating biochemical signals activated by specific mechanical stimuli under 

different loading conditions. 

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Integrative physiology 

Researchers have made considerable progress in understanding interactions between bone 

physiology and the broad network of biologic processes involving various organs and tissues. 

For example, muscle function and muscle mass influence fracture risk and energy metabolism 

affects muscle tissue and bone cells. Scientists are now poised to make further discoveries to 

help explain the connection between the skeleton and other mesenchymal tissues (e.g., fat, 

muscle, cartilage, tendon, ligament), physiologic systems (e.g., nervous, vascular, immune, 

digestive), tissue-specific microbiome, and energy metabolism. Bone likely functions as a target 

and/or regulator as it interacts with various systems during development, aging, and disease. 

Many drugs for conditions putatively unrelated to bone may have unanticipated skeletal effects, 

and bone-building drugs may have unanticipated effects on other tissues. Bone researchers in 

collaboration with interdisciplinary scientists who specialize in other organ systems and 

metabolic pathways could begin to fully define these interactions. These teams should consider 

not only bone but also other organs and systems that associate with bone as an integrative unit. 

They should also seek to understand how inputs from multiple systems received by the bone 

affect the body. 

Broad areas of potential research directions include: 

Bone physiology and energy metabolism 

• Characterizing factors that determine whether mesenchymal progenitor cells 

differentiate into osteoblasts or adipocytes; 

• Determining how body mass and composition influence bone homeostasis and 

strength, including the relationship between bone physiology and regulation of 

distinct fat depots (e.g., subcutaneous, visceral, marrow fat); and 

• Elucidating the relationships among bone physiology, obesity, and energy/glucose 

metabolism. 

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Bone and the nervous system 

• Determining the mechanisms by which the central and peripheral nervous systems 

influence bone physiology, including the influence of circadian rhythms on the 

skeletal system; and 

• Defining the roles of neurotransmitters and neuropeptides in bone. 

Bone and the hematopoietic and immune systems 

• Clarifying the importance of interactions between bone cells and cells of the 

hematopoietic system, and of the innate and adaptive immune systems in both bone 

health and disease, including components of bone marrow that influence bone 

physiology and bone remodeling; 

• Defining functions of regulatory molecules that may affect both bone physiology and 

immune system development and function; and 

• Examining mechanisms underlying bone destruction during inflammation and 

autoimmunity. 

Bone and the vascular system 

• Determining the relationship between angiogenesis (the formation of new blood 

vessels) and the processes of bone growth and remodeling; and 

• Exploring possible parallels and interactions between bone mineralization and 

vascular calcification in cardiovascular disease. 

Bone and cancer 

• Exploring interactions between cancer cells and bone cells during bone metastasis; 

and 

• Elucidating mechanisms that underlie skeletal morbidity associated with malignancy, 

such as pathological bone resorption and formation. 

Bone as a component of joints 

• Characterizing the interface and crosstalk between bone and cartilage in articular 

joints, including signals originating in bone that may contribute to osteoarthritis; 

• Determining distinct or overlapping roles of bone and connective tissue in conferring 

benefits of physical activity, including responses to mechanical stimuli and 

interaction with energy metabolism and mitochondrial function; 

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• Defining mechanisms that lead to pathological bone formation in joints, such as 

osteophytes (bone spurs) or spinal stenosis; and 

• Describing the structure and function of bone, ligaments, and tendons, as well as the 

joint interphase formation and mechanisms leading to enthesopathy. 

Bone and muscle 

• Elucidating molecular and cellular communication pathways between bone and 

muscle, such as endocrine factors, neural influences, and exosomes; 

• Determining distinct or overlapping roles of bone and muscle in conferring benefits 

of physical activity, including responses to mechanical stimuli and interactions with 

energy metabolism and mitochondrial function; 

• Exploring synergies among therapeutic approaches that could yield improvements in 

the health and function of bone and muscle tissue; and 

• Identifying differences and parallels in injured bone and muscle healing, including the 

origins of progenitor cells contributing to tissue regeneration. 

Skeletal development and homeostasis 

Bone shaping and growth during infancy and childhood are important for adult skeletal health. 

Research into processes by which bones originate in the embryo and grow during skeletal 

maturation promises to illuminate causes and potential treatments of developmental disorders in 

humans. This knowledge may lead to more effective methods for enhancing repair and 

regeneration of bone damaged by disease or trauma. Bone cells arise from specialized progenitor 

or stem cells that can differentiate to produce several types of cells in response to various 

biochemical signals. Understanding these cells and the signals that guide them could improve 

tissue engineering and regenerative medicine approaches. Stem cells are also important targets of 

gene-based therapy strategies for genetic diseases of bone. 

Broad areas of potential research directions include: 

Early skeletal formation and growth 

• Determining the mechanisms that establish bone location and shape during embryonic 

development; and 

• Exploring environmental factors that affect bone during growth and development. 

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Disorders of skeletal development 

• Defining causal factors underlying skeletal development disorders, such as the 

osteochondrodysplasias and other rare bone diseases, to understand the role of 

specific genetic mutations that contribute to skeletal disorders; and 

• Investigating biological mechanisms that are associated with mutations linked to 

skeletal development disorders, including cellular and molecular consequences of 

these genetic changes on developmental processes. 

Stem cells 

• Mesenchymal/skeletal progenitor cells 

o Defining mesenchymal cell lineages to identify multipotent precursors with 

osteogenic potential; 

o Exploring the role of tissue origin (e.g., marrow, adipose, or periosteum) on 

differentiation potential; 

o Developing cell lineage markers to identify stages of osteogenic and 

chondrogenic differentiation; 

o Defining the contribution of different populations of stem cells to the 

development and formation of bone structure; and 

o Investigating effects of regulatory factors, such as growth factors and bone 

morphogenetic proteins, on proliferation and differentiation of progenitor cells. 

• Embryonic and pluripotent stem cells 

o Examining osteogenic differentiation of animal and human embryonic stem cells, 

including responses to growth factors and other regulatory molecules; and 

o Exploring the potential of iPS cells for differentiation along the osteogenic 

pathway, including differences between induced and embryonically derived stem 

cells and the effects of different strategies for inducing pluripotency. 

Genetics, genomics, and epigenetics of bone mass and fracture risk 

Heredity influences many aspects of skeletal physiology, including age-associated changes. 

Although genetic influences on the skeleton are complex, reflecting the contributions of 

numerous genes and post-transcriptional epigenetic modifications, technological advances have 

opened the door to an unprecedented understanding of individual risk for disease as well as 

personalized approaches to treatment. In recent years, high-throughput genotyping and 

sequencing technologies have been employed to analyze many clinical cohorts, largely 

substantiating the potential of genomic science to illuminate questions in skeletal biology and 

health. 

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Nonetheless, much of the heritability of skeletal traits, such as bone mass and fracture risk, 

remains to be identified. In addition, causal variants underlying skeletal disease, as well as the 

biochemical processes influenced by those variants, are still largely unknown. Filling in these 

gaps will require an integrated analytical approach, incorporating multiple data types (e.g., 

single-cell analysis, epigenomics, proteomics, transcriptomics, machine learning, computational 

modeling) and large sample sizes to reveal functional aspects of the genome in humans and in 

animal models. 

Broad areas of potential research directions include: 

Functional genomics and epigenomics of skeletal cells and tissues 

• Acquiring and making broadly available data reflecting the functional state of the 

genome (e.g., transcriptional activity, epigenetic characteristics) in cells of bone and 

cartilage; 

• Characterizing genetics and epigenetics of skeletal cells, including their roles in cell 

functions at the single-cell level; 

• Identifying causal variants and molecular mechanisms that influence skeletal traits; 

• Continuing to define genetic differences that underlie variation in bone formation, 

maintenance, and turnover; 

• Integrating insights from animal models with data from human studies to determine 

functional significance of specific coding and noncoding gene regions; and 

• Applying systems biology methodologies, big data approaches, computational 

modeling, and artificial intelligence to the study of skeletal biology, as well as 

making use of big data resources, such as ENCODE and GTEx. 

Translating genomic insights into skeletal health 

• Determining mechanisms of genotype-phenotype interactions and variations on bone 

health; 

• Utilizing genetically modified skeletal systems and bone cells to develop therapeutics 

to address genetic defects; 

• Exploring how environmental exposures and aging interact with genetics, leading to 

bone disease; and 

• Identifying genetic and epigenetic markers that predict drug responses of bone tissues 

and cells. 

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Mechanisms of bone diseases: Preclinical and translational research 

Pathobiological/pathophysiological mechanisms 

Discovering the underlying pathobiological and pathophysiological basis of bone diseases will 

advance the field of bone biology. Interactions between laboratory and clinical researchers are 

essential for translating basic discoveries into new drugs, treatments, and diagnostics. These 

relationships also foster clinical observations that can prompt basic and translational research. 

Broad areas of potential research directions include: 

Mechanisms of bone loss, disease, and regeneration 

• Characterizing molecular and cellular mechanisms contributing to bone loss during 

common physiological conditions such as sex-hormone deficiency, vitamin D 

insufficiency, chronic inflammation, and steroid drug treatment; 

• Defining biological mechanisms underlying the pathology of rare bone diseases, such 

as osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and Paget’s disease 

of bone; 

• Applying knowledge of potential therapeutic targets to develop and test new 

interventions for rare bone diseases; 

• Identifying differences and parallels in injured bone and connective tissue healing, 

including the origins of progenitor cells contributing to tissue regeneration; 

• Investigating mechanisms of increased bone loss or fracture risk due to diseases of 

other organs and systems, such as HIV infection or diabetes, or due to inactivity or 

unloading as a consequence of aging, dementia, or other diseases or conditions that 

cause a patient to be bedridden; and 

• Investigating mechanisms of bone regeneration and repair, the cells and signaling 

involved, and other factors that determine the success or failure of the repair process. 

Treatment-related mechanisms or processes 

• Elucidating biological processes that contribute to bone loss surrounding orthopaedic 

implants and developing bone-preserving strategies for implant recipients; and 

• Examining potential mechanisms of rare adverse effects associated with 

bisphosphonates and other osteoporosis drugs, such as atypical femoral fractures. 

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Model systems 

• Developing preclinical animal models that more accurately represent initiation and 

progression of bone disease in humans, including response to therapies and potential 

adverse effects; and 

• Developing new models, such as organoid systems, to improve understanding of the 

effects of variants associated with disease. 

Therapeutic mechanisms 

Translational research characterizing the cellular and molecular mechanisms of disease may lead 

to new biological insights that advance the diagnosis or prevention of bone disease and inform 

the development of novel therapeutic agents. 

Broad areas of potential research directions include: 

Underlying biological mechanisms 

• Defining biological mechanisms of action for widely used medications, such as drugs 

prescribed to prevent or reverse bone loss, including adverse effects (e.g., atypical 

femoral fractures); 

• Examining why some therapeutic agents become less effective with long-term use; 

and 

• Translating knowledge about mechanobiology and bone response to loading into 

strategies for promoting bone health, fracture healing, and bone defect repair across 

the lifespan. 

Drug discovery targets and their potential 

• Identifying molecular targets for new drug treatments with greater efficacy and less 

adverse effects; 

• Exploring multimodal therapeutic approaches to treat osteoporosis; and 

• Determining bone effects of drugs prescribed for diseases of other tissues and 

systems, which may have an impact on bone quality or fracture risk. 

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Gene-based therapies 

• Developing methods for recovery and re-introduction of cells in the marrow 

stromal/osteoblast lineage; 

• Exploring the potential of embryonic and iPS cells as mediators of gene-based 

therapies for disease of bone; 

• Discovering innovative ways to use genetic modification of cells to correct genetic 

defects in bone or to manipulate gene expression for therapeutic purposes; and 

• Establishing gene-inactivation methods using various strategies such as viral vectors, 

small interfering RNAs, and genome editing. 

Imaging and biomarkers of bone quality and fracture risk 

Noninvasive measures of bone quality and fracture risk 

Measuring bone mineral density (BMD) is widely considered a good screening tool for 

osteoporosis, but is an imperfect test for assessing the strength and fracture resistance of bone. 

BMD does not account for specific contributions of bone geometry, microarchitecture, and 

material properties that influence the ultimate mechanical performance of bone. Dual energy Xray absorptiometry (DXA), the standard clinical measurement of BMD, is widely available and 

economical. However, more sensitive and sophisticated methodologies have been developed and 

provide a more detailed picture of bone quality and strength, such as quantitative computed 

tomography (QCT) with finite element analysis, high-resolution peripheral QCT, and high-field 

magnetic resonance imaging (MRI). The application of these newer technologies has improved 

our understanding of bone structure and function, but has not yet provided an alternative method 

for assessment of osteoporosis. Further studies may lead to improved prediction of fracture risk 

and monitoring of treatment response. 

Broad areas of potential research directions include: 

In vivo methods 

• Improving existing in vivo methods to assess bone loss, response to treatment, and its 

relationship with surrounding tissues, such as fat and muscle; 

• Applying novel technologies and methodologies in large cohorts of normal, at-risk, 

and diseased individuals to examine the connections among bone, fat, and muscle 

tissue; 

• Developing and validating noninvasive methods to assess bone quality, such as 

magnetic resonance, QCT, infrared imaging, and ultrasound; 

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• Developing algorithms to improve the clinical assessment of fracture risk and to 

provide early indications of treatment effectiveness; and 

• Developing and adapting existing noninvasive tools to assess essential 

musculoskeletal functions, including biomechanical aspects of bone and muscle. 

Integrating and improving imaging methods 

• Developing new technologies for enhanced high-resolution imaging of bone ex vivo; 

• Developing methods to integrate data from various in vivo and ex vivo imaging 

methods; and 

• Building prediction models for disease risk from various imaging methods. 

Therapeutic targets 

Understanding how architectural, material, and biochemical factors contribute to bone strength 

may identify new treatment targets or novel markers of bone health. 

Broad areas of potential research directions include: 

Biological marker studies 

• Identifying biochemical markers of bone strength and fracture risk that can be 

measured in easily obtainable biospecimens, such as blood or urine; 

• Investigating the utility of exosomes as bearers of tissue-specific biomarkers; and 

• Validating candidate biomarkers in well-characterized clinical cohorts for which bone 

mass, bone quality, and fracture risk can be assessed independently. 

Clinical research for rare bone diseases 

Observational studies for rare bone diseases 

In addition to basic and translational pathophysiological research, the NIAMS Bone Biology and 

Bone Diseases program supports clinical research to advance the diagnosis, management, and 

treatment of rare bone diseases. Knowledge of disease development and progression, diagnostic 

tools, and therapeutic options vary across the rare bone diseases. Rare bone diseases often 

manifest in organ systems other than the bone and musculoskeletal systems. Thus, 

multidisciplinary research efforts that incorporate integrative physiology approaches to study 

comorbid conditions are encouraged. Further, because of the limited number of patients affected 

by these diseases, innovative clinical study designs are necessary. To accelerate research, 

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patients and patient advocacy groups are important partners and should be engaged throughout 

the clinical research process. 

Broad areas of potential research directions include: 

Natural history studies 

• Conducting natural history studies in rare bone diseases using common data elements 

whenever possible to document disease progression, the range of disease 

manifestations, and response to existing treatment and disease management, including 

those that address unmet clinical trial readiness needs and development of outcome 

measures; and 

• Documenting how the diseases affect patients’ function, such as loss of independence 

and pain, using methodologies such as patient-, parent-, or physician-reported 

outcome measures. 

Phenotype-genotype and biological marker studies 

• Studying phenotype-genotype interactions/relationships; and 

• Validating clinical or biological markers for disease development, progression, and 

therapeutic outcomes, including occurrence of side effects, to support the clinical 

development of new therapeutics. 

Therapeutic development and intervention studies 

There is great need for discovery of therapeutic interventions for rare bone diseases. 

Broad areas of potential research directions include: 

Drug development, characterization, and validation 

• Developing novel therapeutics for rare bone diseases with greater efficacy and fewer 

adverse effects; 

• Adapting and repurposing therapies developed for other diseases to treat rare bone 

diseases; and 

• Characterizing and validating new therapies to determine their efficacy and safety 

profiles, using innovative trial designs to address the issue of scarce and precious 

patient resources. 

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Responses to therapeutic intervention 

• Optimizing existing therapies through investigating different dosing, timing, and 

delivery system (pharmacokinetics); 

• Determining responses to therapeutic interventions at multiple specific drug 

concentrations (pharmacodynamics) and their underlying mechanisms of action; and 

• Determining how specific drugs interact with particular genetic alleles 

(pharmacogenomics). 

Nonpharmacologic interventions 

• Developing nonpharmacologic interventions such as physical activity, dietary 

modifications, and behavioral or biopsychosocial approaches to improve function and 

alleviate pain; and 

• Involving patients and patient advocacy groups in the process of therapeutic 

development to determine feasibility and acceptability of interventions. 

Outcome measures 

• Incorporating outcome measures that indicate therapeutic effects on bone as well as 

other musculoskeletal systems and organ systems, considering therapeutic effects on 

the extra musculoskeletal system as a whole; 

• Developing and validating biomarkers to predict patients’ responses to therapies, 

including efficacy outcomes and potential adverse effects; and 

• Incorporating patient- and physician-reported outcome measures in clinical design. 

Clinical research for osteoporosis 

Observational studies for osteoporosis 

Characterizing osteoporosis development through clinical research is necessary to decrease 

prevalence, alleviate suffering, and lessen economic costs. Utilizing individual and populationbased data to determine disease effects will enable better prevention approaches, produce safer 

therapies, improve quality of life, facilitate earlier identification of those at high risk, and reduce 

disparities associated with osteoporosis. Both large cohort and personalized medicine studies can 

yield useful information to improve bone health, prevent and treat osteoporosis, and enhance the 

quality of life of the millions of Americans who develop this disease. 

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Broad areas of potential research directions include: 

Natural history, cross-sectional, opportunistic studies 

• Identifying critical time points throughout the lifespan that influence susceptibility to 

bone diseases; 

• Determining the role of sex, gender, race, and ethnicity in bone diseases and 

conditions; 

• Understanding the role of pain in chronic skeletal diseases/conditions and on key 

outcomes; 

• Exploring environmental factors (e.g., lead) that may influence bone health and 

disease; and 

• Elucidating factors that contribute to fragility fractures. 

Outcome measure development 

• Developing prediction models for bone health, bone disease, and response to 

treatment that incorporate risk versus benefit analysis and patient preferences; and 

• Enhancing development and validation of outcome measures, including incorporation 

of predictive biomarkers for efficacy or adverse effects and patient preferences. 

Intervention studies for osteoporosis 

Intervention studies to prevent and treat disease are essential to bring basic knowledge and 

translational research into clinical guidelines and practice. NIAMS recognizes the importance of 

maintaining wellness in healthy populations and enhancing the well-being of individuals with 

bone disorders or diseases. Because motivating behavior change at a population level is an issue 

facing many NIH components, it may be possible to integrate research on bone health messages 

with other health promotion programs, such as dietary and exercise interventions. Novel study 

designs are needed for both prevention and treatment of osteoporosis. In addition, engaging 

patients and participants is essential to developing effective osteoporosis prevention studies and 

health promotion programs. 

To better characterize specific research needs related to osteoporosis interventions, NIAMS 

participated in an NIH Pathways to Prevention effort, described in the box below. 

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NIH Pathways to Prevention Workshop: Appropriate Use of Drug Therapies for 

Osteoporotic Fracture Prevention 

More than 10 million people in the United States have osteoporosis. Lifestyle changes, 

including exercise and a healthy diet, may help reduce a person’s risk of fracture. However, 

medications are often needed to prevent fractures if a person has osteoporosis and are essential if 

a person has experienced a previous fragility fracture. Effective FDA-approved medications can 

prevent debilitating and sometimes life-threatening fragility fractures. Reducing osteoporosis 

prevalence and hip fracture incidence are among the major objectives of Healthy People 2020 

and 2030, the U.S. Department of Health and Human Services’ national health promotion and 

disease prevention initiatives. 

1 

Rigorous clinical studies have demonstrated that 3 to 5 years of osteoporosis medication therapy 

prevents fractures. Clinical guidelines recommend bisphosphonates as a first line of treatment for 

most people who have osteoporosis, but treatment rates are low and medication adherence is 

poor. Reports of rare but serious adverse events and greater public concern about them have 

coincided with a marked decrease in the use of osteoporosis drugs and a leveling off in what had 

been a promising decline in the incidence of osteoporotic fractures. 3 Furthermore, as 

osteoporosis is considered a lifelong condition, the use of medications continues to be the 

cornerstone of therapy for osteoporosis. However, the benefits and risks of long-term 

osteoporosis drug therapies are not fully known. 

2,

In October 2018, NIAMS, the National Institute on Aging, and the NIH Office of Disease 

Prevention hosted a Pathways to Prevention Workshop on the Appropriate Use of Drug 

Therapies for Osteoporotic Fracture Prevention to identify research gaps and suggest focus areas 

that could move the field forward. As part of the workshop process, based on an Agency for 

Healthcare Research and Quality (AHRQ) systematic review of the scientific evidence, speaker 

presentations, audience input, and public comments, an independent panel issued a report that 

lays the foundation for future research activities. Strategies for disseminating and implementing 

these findings will be developed by federal agencies to improve public health in FY 2020 and 

beyond. 

5 

4

1 Wright NC, et al. J Bone Miner Res. 2014. PMID: 24771492. 2 Wysowski DK, et al. Bone. 2013. PMID: 24063946. 3 Michael Lewiecki E, et al. Osteoporos Int. 2017. PMID: 29282482. 4

 Fink HA, et al. Ann Intern Med. 2019. PMID: 31009947. 5

 Siu A, et al. Ann Intern Med. 2019. PMID: 31009943. 

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Broad areas of potential research directions, many of which are consistent with the 

recommendations from the Pathways to Prevention workshop, include: 

Prevention 

• Developing new therapies to prevent fractures associated with osteoporosis and 

related conditions, including behavioral or biopsychosocial approaches, such as 

exercise, nutrition intervention, and biofeedback; 

• Determining the impact of nutritional status (e.g., macronutrients and micronutrients 

such as vitamin D) on bone health and fracture risk; 

• Developing and testing strategies to promote bone health and prevent osteoporosis by 

improving nutritional status on a population level; 

• Exploring effects of environmental factors, such as smoking and environmental 

toxins, on skeletal health and development of osteoporosis; and 

• Developing and validating improved outcome measures for osteoporosis prevention 

interventions. 

Treatment 

• Assessing combinations of existing therapeutic agents to achieve additive or 

synergistic treatment benefits; 

• Improving adherence to clinical protocols by developing and testing less burdensome 

dosing regimens or routes of administration (e.g., direct delivery to the skeleton) and 

exploring approaches that reduce side effects from drugs; 

• Comparing the effectiveness of different therapeutic approaches; 

• Developing and validating novel outcome measures and surrogate markers that could 

be used to improve clinical trial efficiency; 

• Developing new therapies to treat osteoporotic fractures and related conditions in 

research areas that might include: 

o Behavioral/biopsychosocial (e.g., exercise, rehabilitation); 

o Pharmacologic: antiresorptive, anabolic, combination/mixed therapies; and 

o Combinatorial approaches; 

• Developing new therapies to implement following a primary fragility fracture to 

prevent future fractures, such as behavioral and biopsychosocial interventions, 

pharmacological treatments, or combinatorial approaches; 

• Optimizing dosing and length of therapeutic interventions to maximize clinical bone 

outcomes; 

• Identifying patient subpopulations that will benefit the most from therapies and 

improving the rate of drug initiation in those populations; 

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• Developing models assessing the balance between risk and benefit for both short- and 

long-term osteoporosis therapies; and 

• Developing effective drug holiday strategies to maximize therapy benefit while 

minimizing adverse effects. 

Personalized medicine in osteoporosis clinical studies 

Characterizing disease mechanisms in clinical studies may enable researchers and health care 

providers to distinguish among disease subtypes that have similar endpoints (e.g., fracture). 

Further, improved understanding of individual genetic variation in osteoporosis is expected to 

lead to better prediction of drug response and account for heterogeneity in response to treatment. 

Existing databases can be retrospectively mined for information about variations in disease 

manifestation and treatment response. 

Broad areas of potential research directions include: 

Interaction of biologic and environmental factors 

• Developing improved predictors of fracture risk that reflect the contribution of the 

individual’s environment, lifestyle (physical activity and dietary intake), the 

microbiome, and personal medical history; 

• Examining variability in treatment response and determining mechanisms to explain 

disparate responses (e.g., why some patients are refractory to certain treatments and 

why some develop serious side effects); and 

• Investigating effects of genetic variation on treatment response. 

Drug interactions with other factors 

• Exploring interactions between bone-active drugs and medications prescribed for 

other co-occurring conditions. 

Dissemination and implementation research toward osteoporosis prevention 

NIAMS recognizes the importance of disseminating and implementing research findings; yet 

such findings may not be widely disseminated or implemented across clinical and community 

health care settings. Behavioral and social science approaches should be incorporated, where 

appropriate, to facilitate their adoption and implementation across diverse populations. 

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Broad areas of potential research directions include: 

Dissemination, communication, and implementation at all levels 

• Improving dissemination, communication, and implementation at the patient, 

physician, and health systems levels to improve diagnosis, prescription, uptake of, 

and adherence to prevention and treatment strategies for osteoporosis. 

Social and behavioral determinants of health 

• Determining patients’ and health care professionals’ beliefs and perceptions regarding 

fracture-associated morbidity and mortality, the benefits and risks of medication, and 

how they compare with the existing evidence; 

• Identifying physician and patient barriers preventing the administration and use of 

pharmacologic therapies by patients at high risk of fracture; 

• Elucidating strategies to increase primary care physicians’ consideration of fracture 

risk and risk/benefit balance of fracture prevention strategies in their evaluation of 

complex patients with comorbid conditions; and 

• Evaluating factors (e.g., legal/liability concerns) that influence primary care 

physicians’ decisions to prescribe pharmacologic therapies. 

Strategies to improve implementation 

• Evaluating cost-effectiveness of various treatments compared with usual care; 

• Exploring the impact of adherence and nonadherence on outcomes; 

• Developing clinical decision-making tools that incorporate risk/benefit modeling to 

facilitate informed and shared decision making between clinicians and patients about 

osteoporotic therapies; 

• Identifying strategies at the patient, physician, and health care systems levels (such as 

fracture liaison services) that can improve diagnosis and treatment of osteoporosis 

and increase adherence of drug therapies; and 

• Tailoring delivery of care to improve health outcomes. 

Health disparities in fragility fracture incidence, treatment, and outcomes 

The emerging links between race, ethnicity, sex, age, disease status, and socioeconomic status 

and bone density, bone quality, and fracture risk suggest areas of genetic, biologic, and 

environmental diversity ripe for exploration. A person’s ethnicity and race, like his or her sex, 

influences the likelihood that he or she will develop osteoporosis and suffer fragility fractures of 

the hip, spine, or wrist. For example, African ancestry is generally seen as protective against 

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fracture, relative to European and Asian ancestry. However, bone health disparities are complex 

across and within groups. The changing demographics of the United States afford numerous 

opportunities for researchers to explore biologic and nonbiologic causes of disparities related to 

fragility fractures and to test strategies to ensure that all Americans benefit equally from efforts 

to monitor and improve bone health. 

Broad areas of potential research directions include: 

Biological influences on bone-related health disparities 

• Investigating how mechanisms of action at the cellular and molecular levels (i.e., 

genetic studies) may vary among populations to affect bone health; 

• Identifying differential responses to therapeutic interventions according to race, 

ethnicity, sex, and their underlying mechanisms; and 

• Characterizing genetic and epigenetic factors that underlie ethnic, racial, and sex 

differences in bone mass, fracture risk, and fracture repair. 

Other influences on bone-related health disparities 

• Identifying barriers to participation of underrepresented populations in bone and other 

clinical research, and implementing strategies to reduce them; 

• Developing and testing culturally relevant patient education materials to improve 

education and outreach in underrepresented populations and improve outcomes; and 

• Evaluating effectiveness of established interventions in minority populations. 

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Advancing and Accelerating Muscle Biology and Diseases Research 

The NIAMS Muscle Biology and Diseases programs encourage basic, translational, and clinical 

research on the biology and disorders of skeletal muscle. Studies address questions about: muscle 

developmental biology, growth, maintenance, and hypertrophy; physiology of muscle 

contraction; structural biology of the contractile apparatus; mechanisms of muscle diseases and 

disorders; biomarkers and outcome measures for clinical and preclinical studies; and natural 

histories of muscle conditions. These programs also support development and testing of therapies 

for muscle diseases and disorders, including cell and gene therapies, small molecule drugs and 

biological products, and exercise and other physical interventions to slow or prevent disease 

progression. 

Muscular dystrophies are an area of emphasis within the NIAMS muscle research portfolio. 

NIAMS participates in the Muscular Dystrophy Coordinating Committee (MDCC), which 

includes stakeholders from federal and private organizations. Research objectives for muscular 

dystrophies are presented in this NIAMS Strategic Plan where they overlap with objectives for 

other muscle diseases. A more specific and detailed description of research objectives for 

muscular dystrophies is found in the MDCC’s Action Plan for the Muscular Dystrophies. That 

plan includes input from experts in the fields of muscular dystrophy pathophysiology, diagnosis, 

treatment, and patient and family care. NIAMS also partners with the National Institute of 

Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute 

of Child Health and Human Development (NICHD), with additional support from the National 

Heart, Lung, and Blood Institute (NHLBI) to fund the Paul D. Wellstone Muscular Dystrophy 

Research Centers program, an evaluation of which is described in the box below. 

Evaluation of the Paul D. Wellstone Muscular Dystrophy Research Centers 

The muscular dystrophies are a group of more than 30 genetic diseases characterized by 

progressive degeneration of skeletal muscles. Many dystrophies also affect other organ systems, 

such as the heart, brain, blood vessels, and gastrointestinal tract. Some forms occur in infancy or 

childhood, while others typically appear later. NIH funds a broad portfolio of research into 

understanding and treating various forms of muscular dystrophy. One component of this research 

portfolio is the Paul D. Wellstone Muscular Dystrophy Research Centers program. 

NIH established a muscular dystrophy Centers of Excellence program in 2003 in response to the 

Muscular Dystrophy Community Assistance, Research, and Education Amendments (MDCARE) Act of 2001, and the centers became the Paul D. Wellstone Muscular Dystrophy 

Cooperative Research Centers in 2008. Although NIH has refined the program over the past 15 

years, the neuromuscular disease research landscape has changed significantly since its 

inception. As the next award competition cycle approached, the principle of good stewardship 

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suggested that a comprehensive review of the Wellstone Centers program was timely and 

important. Therefore, the four NIH Institutes that support the Centers (NIAMS, NINDS, NICHD, 

and NHLBI) formed a Working Group of the NIAMS Advisory Council in FY 2018 to identify 

best practices for achieving the Wellstone Centers’ goals of:

 • supporting impactful basic, preclinical translational, and clinical research in the muscular 

dystrophies through synergistic projects; 

• developing and broadly distributing resources that accelerate muscular dystrophy 

research;

 • facilitating the training of the next generation of muscular dystrophy researchers and 

clinical scientists; and

 • enabling connections with the patient community. 

The Wellstone Centers Evaluation Working Group advised the NIAMS Council, and the report 

was shared with the NINDS, NICHD, and NHLBI Advisory Councils to inform their discussions 

about the Wellstone Centers program, especially the development of Wellstone Center Funding 

Opportunity Announcements. The report’s executive summary, including the working group 

recommendations, is available online. 

Muscle development and regeneration 

Development 

Understanding the process by which functional muscle fibers develop from their early, immature 

state may provide insights into disease mechanisms, regeneration strategies, and therapeutic 

targets. 

Broad areas of potential research directions include: 

• Determining lineage of cells that develop into muscle; 

• Defining factors that influence embryonic cell fate and those that control cell 

proliferation, migration, and differentiation in myogenesis; 

• Elucidating mechanisms underlying myogenic chemotaxis, adhesion, and fusion; 

• Determining when individual myonuclei are incorporated into muscle tissue during 

development and their progenitor cell sources; 

• Identifying and characterizing determinants of tissue patterning (e.g., muscle size, shape, 

fiber composition) during development; 

• Studying formation of the contractile apparatus, myotendinous junctions, and other 

complex structures that make up mature muscle; and 

• Understanding how muscle fibers integrate with other tissues (e.g., adipose tissue, 

immune cells, and tendons) during development. 

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Growth and maintenance 

Studying the behavior of mature muscle under various environmental conditions (e.g., use and 

disuse, health and disease) is critical for developing strategies to repair or regenerate muscle. 

Broad areas of potential research directions include: 

• Characterizing cell types that contribute to muscle growth and maintenance, including the 

activation, migration, proliferation, and differentiation of muscle stem cells, such as 

satellite cells and other progenitors, during cell or tissue turnover and repair; 

• Exploring satellite cell heterogeneity among individual fibers or muscles and among 

species; 

• Determining when individual myonuclei become incorporated into muscle tissue during 

hypertrophy and their progenitor cell sources; 

• Examining gene expression differences among muscle fibers or myonuclei and how they 

affect muscle specialization; 

• Defining factors that regulate gene and protein expression controlling muscle growth, 

fiber type determination, and hypertrophy (e.g., epigenetic changes, microRNAs); 

• Identifying and characterizing modulators of signaling pathways that increase musclefiber growth and cell proliferation (e.g., myostatin inhibitors, IGF1 signaling agonists); 

• Defining genetic variations that enhance or limit normal anabolic responses of skeletal 

muscle to resistance or endurance training or that protect from or exacerbate atrophy or 

cachexia; 

• Investigating tissue, cellular, and subcellular responses to environmental factors 

including exercise, disuse, and nutrition (including the microbiome); 

• Exploring molecular and biochemical factors responsible for differences in muscle mass, 

susceptibility to atrophy, and response to exercise between men and women, people at 

different ages, or people from different racial backgrounds; and 

• Studying the catabolic processes of autophagy and proteolysis as they relate to turnover 

of muscle fiber components. 

Mechanisms of muscle function and dysfunction 

Cell physiology and biophysics 

Studies of normal muscle-cell physiology are likely to uncover new pathways and processes that 

researchers could use to develop treatments for muscle diseases. 

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Broad areas of potential research directions include: 

Excitation/contraction coupling 

• Determining the structure and function of components of the sarcolemma and 

sarcoplasmic reticulum required for muscle cell excitation and intracellular calcium 

handling, including how membranes communicate; 

• Defining calcium’s role in contraction; and 

• Exploring strategies to restore muscle function by optimizing intracellular, 

compartmental, and extracellular calcium and other ion concentrations and 

sequestration. 

Structural biology and biophysics 

• Elucidating the structure and function of macromolecular complexes essential for 

skeletal muscle function and maintenance, including dystrophin/glycoprotein 

complex, contractile apparatus, and ion channel complexes; and 

• Characterizing protein complex assembly in more detail, including the roles of 

chaperones. 

Cellular biomechanics 

• Determining mechanisms by which mechanical stimuli influence muscle assembly 

and turnover; 

• Determining relationships of muscle protein synthesis and force production during 

hypertrophy and atrophy; 

• Characterizing in further detail how the contractile apparatus and links to the extracellular matrix are modulated during fiber repair and regeneration; and 

• Investigating how muscle-strain injuries affect the components and organization of 

macromolecular complexes. 

Mitochondrial biogenesis, turnover, and function 

• Understanding better the control of muscle mitochondrial function and turnover in 

normal and disease states; 

• Understanding effects of exercise on mitochondrial biogenesis; and 

• Enhancing understanding of muscle mitochondrial function and uncoupling in energy 

metabolism. 

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Integrated physiology and metabolism 

The mechanisms by which muscle activity directly or indirectly contributes to the causes, 

prevention, and treatment of diseases and disorders affecting the musculoskeletal and other organ 

systems are a promising area of inquiry. For example, better understanding of the processes 

connecting muscle activity in the context of physical activity to disease prevention/amelioration 

may contribute to the use of exercise as a treatment for non-muscle related health conditions. 

Broad areas of potential research directions include: 

Muscle as an endocrine organ and metabolic tissue 

• Defining metabolic and hormonal interactions between muscle and other tissues 

during normal, exercised, and diseased states; 

• Examining muscle’s role as a heat-producing organ in the regulation of core 

temperature; 

• Exploring environmental effects and gene-environment interactions on muscle 

function; 

• Identifying and characterizing factors released into circulation during skeletal muscle 

activity that affect other tissue and organ systems; and 

• Investigating compounds that improve muscle’s ability to metabolize energy sources. 

Immune and inflammatory responses 

• Characterizing positive and negative effects of inflammation on muscle regeneration 

after exercise, injury, or disease; and 

• Determining mechanisms by which exercise alters immune responses. 

Kinesiology 

• Understanding muscle and muscle connective tissue interactions and the potential role 

of associated structural molecules; 

• Improving understanding of how mechanical function of individual muscles 

determines energy use; and 

• Determining how individual muscle recruitment affects gait and motion. 

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Pathophysiology 

Just as research on normal muscle physiology is likely to uncover new treatment targets, a better 

understanding of how specific molecular defects produce the abnormal phenotypes of muscle 

diseases will provide insights into normal muscle function. 

Broad areas of potential research directions include: 

Mechanisms of single gene muscle diseases 

• Identifying gene mutations associated with muscle diseases with unknown causes; 

• Characterizing genotype-to-phenotype correlations for muscle diseases; 

• Understanding mechanisms of diseases caused by single-gene mutations, such as 

muscular dystrophies and channelopathies; 

• Characterizing disease mechanisms to uncover potential therapeutic targets and better 

understand normal muscle biology; 

• Elucidating how defects in gene expression (including epigenetic modifications) and 

post-transcriptional processing—including splicing, transcript modification, 

localization, and transcript stabilization or degradation—contribute to muscle disease; 

• Understanding how defects in post-translational processing, such as glycosylation, 

contribute to muscle disease; 

• Elucidating and examining factors, such as modifier gene variations and epigenetic 

changes, responsible for variation between and within muscle diseases, including 

disease onset, progression, and muscle groups affected; and 

• Identifying compensatory gene products (e.g., utrophin for mutated dystrophin) and 

developing strategies to control their expression, accumulation, localization, and 

activity. 

Muscle impairment associated with complex diseases and conditions 

• Exploring mechanisms of muscle atrophy during prolonged bed rest or disuse often as 

a consequence of injury or critical illness such as cancer; 

• Investigating skeletal muscle changes in cachexia in the context of diverse conditions 

including AIDS, cancer, chronic obstructive pulmonary disease, congestive heart 

failure, and end-stage renal disease; 

• Identifying and characterizing shared signaling pathways associated with downstream 

pathologies (such as weakness and muscle wasting) common to many genetic and 

acquired diseases; 

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• Studying disorders arising from environmental factors, including statin-induced 

myopathies, to understand the genetic and environmental factors contributing to these 

conditions; 

• Investigating mechanisms underlying muscle fatigue; 

• Characterizing genetic and gene-environment interactions associated with complex 

muscle diseases such as inflammatory myopathies; and 

• Studying the role of muscle in inflammatory myopathies to facilitate development of 

effective interventions. 

Fibrosis and scarring 

• Elucidating cellular and molecular events that contribute to, or prevent formation of, 

fibrosis and scarring during disease progression and in response to injury; 

• Determining whether muscle fibrosis is a reversible event and understanding steps 

involved in this process; and 

• Characterizing genetic modifiers of muscle fibrosis and scarring and testing gene 

products as potential therapeutic targets or prognostic biomarkers. 

Interventions for muscle health 

Development and use of model systems 

Researchers can use model systems to define muscle development, function, and repair in 

healthy and disease states as well as to test approaches for preventing disease onset and 

progression. These models can be in vivo (animal), in vitro (cell culture or isolated tissue), or in 

silico (computer-based). 

Broad areas of potential research directions include: 

Animal models for understanding disease mechanisms and testing therapeutics 

• Developing and characterizing mouse models of muscle injury, regeneration, and 

disease that more accurately reflect the genetics, pathophysiology, or clinical 

phenotypes observed in humans; 

• Using non-mouse, genetically tractable developmental model systems, such as 

zebrafish, fly, and worm, to understand the genetics and cellular biology of normal 

and disease muscle; 

• Establishing additional mid-size and large animal models to facilitate preclinical 

testing of candidate therapeutics in biological systems closer to the dimensions, 

biomechanical forces, and immune responses of humans; and 

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• Improving assays for characterizing animal models including enhanced in vivo 

imaging capabilities 

Cell models 

• Enhancing strategies for culturing, expanding, and differentiating various primary 

muscle and muscle stem cell models (e.g., satellite cells, iPS-derived myoblasts) for 

use in basic research studies and potential therapeutic applications; 

• Creating human cell models (including 3D and tissue chip systems) that mimic in 

vivo conditions to study disease mechanisms and pathophysiology; 

• Developing additional assays capable of reporting on muscle cell health and function 

including high-throughput, -omic, and live cell-imaging-based approaches; and 

• Making cell models from individuals to enable personalized-medicine strategies and 

allow identification of compounds to which those individuals respond. 

Computational models and artificial intelligence to study muscle function 

• Developing computational models of muscle protein function to understand how 

genetic variants lead to muscle dysfunction and disease; 

• Integrating models of inflammatory pathways in muscle for the identification of 

biomarkers and therapeutic targets for muscle disorders; 

• Using human genomic approaches and computational modeling to develop a systemslevel understanding of the role of muscle in health and disease; 

• Improving models of muscle contraction and physiology from single muscles to 

multiple tissue types and their interactions (multi-scale models); and 

• Modeling disease progression and treatment response to inform more effective and 

efficient clinical trial design. 

Therapeutic interventions 

Several candidate therapies for muscle diseases, especially muscular dystrophies, have emerged 

in recent years. These include small molecules that act on cell or molecular processes, biologics 

such as antibodies or enzymes, gene and cell approaches, nucleic acids (e.g., oligonucleotides), 

as well as nutritional, behavioral, and mechanical interventions. In addition to the development 

of interventions specific for muscle, drugs for other conditions are being tested for muscle 

applications (a process called drug repurposing). The FDA has approved two therapies for 

Duchenne muscular dystrophy in the last 5 years, and several additional candidate therapies for 

muscle diseases, such as gene therapy approaches for muscular dystrophies, are rapidly moving 

into human clinical trials. 

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Broad areas of potential research directions include: 

Developing, repurposing, and enhancing interventions through: 

Small molecule drugs 

• Developing assays for high-throughput screening (including ‘omics technologies) 

based on known mechanisms of muscle diseases to target pathophysiology (including 

resources such as the NIH Molecular Libraries and Imaging Program and NCATS 

Bridging Interventional Development Gaps Program); 

• Using rational drug design or computational modeling to design novel small-molecule 

interventions based on molecular understanding of the pathogenesis or 

pathophysiology of muscle disorders; and 

• Exploring public-private partnerships that increase the likelihood of successfully 

developing candidate therapeutics. 

Biologics 

• Developing biologics to treat muscle diseases based on activity of growth factors, 

extracellular matrix proteins, enzymes, and other gene products; 

• Characterizing isoforms, subcomponents, metabolites, and mechanisms of action of 

potential therapeutic proteins and other biologics; 

• Applying enzyme-replacement therapies beyond glycogen-storage diseases, and 

developing strategies to prevent or manage immune response to enzyme-replacement 

therapy; 

• Developing therapeutics that enhance muscle strength and resistance to fatigue; and 

• Identifying and testing therapeutics that enhance or replace effects of exercise 

training on skeletal muscle. 

Gene transfer and genome editing therapies 

• Characterizing properties of gene delivery vectors (viral and nonviral) to select those 

that facilitate efficient delivery of therapeutic genes to prescribed muscles of the body 

and minimize immune responses and delivery to unintended tissues; 

• Continuing to develop approaches to control gene activity (e.g., regulatory cassettes) 

that maximize expression of therapeutic genes in specific target tissues; 

• Developing a more thorough understanding of immune responses to gene transfer and 

genome editing therapies and designing interventions that avoid or minimize immune 

responses following initial and repeated delivery of therapeutic genes; 

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• Developing methods to assess and predict safety and efficacy of genome editing as it 

pertains to muscle disorders; and 

• Advancing strategies for preparation of gene therapeutics that increase scale of 

production, reduce costs, and optimize purity and activity. 

Cell therapies 

• Characterizing abilities of growth factors, extracellular matrix molecules, scaffolds, 

or transcription factors to promote engraftment, survival, proliferation, and 

differentiation of cells that participate in muscle regeneration; 

• Comparing migratory and regenerative potential of different cell types to establish 

characteristics associated with expansion, migration, differentiation, and stability of 

muscle cells and with long-term maintenance and function of muscle tissue for 

clinical studies; 

• Producing markers for tracking long-term outcomes of cell-based muscle therapies in 

animal models or in people with muscle disorders; 

• Studying immune responses in muscle to transplanted cell types and factors in the 

environment of diseased or injured muscle that affect engraftment; and 

• Exploring strategies for genetic manipulation of potentially therapeutic cells by viral 

vectors, genome-editing technologies (e.g., CRISPR/Cas, TALENs), or other 

approaches to correct mutations or otherwise enhance regenerative capacity. 

Molecular therapies (including oligonucleotides) 

• Continuing to develop oligonucleotides and other strategies to modulate the 

expression of gene products with the goal of compensating for mutations and 

restoring functions of proteins necessary for healthy muscle; 

• Developing chemistries to synthesize and modify molecular therapies to improve 

their delivery and uptake by skeletal muscle, heart, and other affected tissues; and 

• Characterizing gene products from exon-skipping strategies and evaluating the ability 

of those products to restore normal muscle function. 

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Nutritional and behavioral interventions, including exercise 

• Leveraging knowledge about effects of mechanical stimuli on healthy and diseased 

muscle to develop biomechanical interventions; 

• Studying mechanisms of exercise with the goal of developing physical activity-based 

interventions attractive to and convenient for people; and 

• Investigating the response of muscle to feeding and nutrition, with and without 

exercise, including the timing of the intervention. 

Devices 

• Enhancing existing and developing novel devices for measuring muscle function, 

dysfunction, and health, and potential application of devices such as electrical 

stimulators in blunting atrophy or muscle degeneration; and 

• Investigating devices (including but not limited to scaffolds) to improve therapy 

manufacturing or efficient delivery to muscle. 

Combination therapies 

• Investigating therapies that may have complementary or synergistic effects when used 

in combination, including determining optimal timing, dosing, and duration of 

treatment; and 

• Exploring whether certain treatments may have antagonistic or detrimental effects 

when used in combination and ways to avoid or mitigate these consequences. 

Muscle disease clinical research 

Observational and natural history studies and clinical tool development 

Observational cohort studies comprised of patients who have muscle diseases can provide 

essential information about disease symptoms, stages, and timing of disease progression, 

comorbid conditions, and outcomes that are important to patients. The development of 

biomarkers, clinical tools, and outcome measures could also inform clinical trials that are more 

efficient. 

Broad areas of potential research directions include: 

Diagnosis, natural history, and genetic modifiers 

• Establishing rapid, precise, and cost-effective methods of diagnosing muscle diseases; 

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• Determining incidence and prevalence of muscle diseases in racial and ethnic groups; 

• Conducting natural history studies to characterize patient phenotypic variations, 

disease course, and comorbid conditions, especially for diseases that have not been 

previously studied in this way; 

• Identifying genetic modifiers that contribute to differences in muscle mass and 

strength, efficiency of muscle repair, susceptibility to atrophy or disease, and 

treatment response; and 

• Applying known genetic modifiers in models and studies investigating genetic 

determinants of disease progression, and as a foundation for developing personalized 

medicines. 

Biomarker discovery, characterization, development, validation, and use 

• Continuing to discover, characterize, and validate diagnostic, monitoring, 

pharmacodynamic/response, predictive, prognostic, and safety biomarkers from an 

array of sources and approaches; 

• Developing additional or enhanced imaging biomarkers through collaboration with 

imaging physicists, bioinformatics experts, or others, that are noninvasive and 

provide information about the size, shape, structure, composition, physical properties, 

and metabolic function of whole muscles or muscle groups; 

• Integrating approaches such as elastography or electrical impedance myography into 

development of biomarkers that reflect physical properties of skeletal muscle; and 

• Integrating biomarker data into databases and computational models that include 

standardized, common data elements to facilitate comparisons between the 

biomarkers and physical functioning and clinical outcomes within the study and 

across other studies. 

Outcome measures (clinical and surrogate) 

• Developing and validating outcome measures that span the entire course of disease to 

allow a wider range of patients to participate in clinical studies; 

• Developing sensitive, accurate, and robust assays to measure proteins and other gene 

products from muscle biopsies and assess the restoration of these products; 

• Refining measurement of muscle contraction, force production, musculoskeletal 

function, motor control, and other physiological functions (including physical 

activity) in a robust and unbiased way; 

• Developing quantitative, noninvasive surrogate markers that can predict changes in 

physical function, disease severity, development of complications, or treatment 

response; 

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• Relating outcome measures and markers to meaningful changes in how an individual 

feels or functions as well as feasibility of including these measures and markers in 

clinical trials; and 

• Improving and enhancing patient-reported outcome measures (PROs) for specific 

muscle diseases by incorporating patient input into PRO development and validating 

PROs developed for other diseases or conditions in people who have muscle diseases. 

Care delivery and socioeconomic factors 

• Evaluating patient transition to independence in adulthood, level of care, and 

accessibility of care, and using these data to develop testable hypotheses to reduce 

burden of muscle disease and improve quality of health services for patients of all 

ages; and 

• Exploring how clinical care and management of patients with muscle diseases is 

influenced by socioeconomic factors, geographic locations, and other demographic 

variables. 

Clinical trials for muscle diseases 

Numerous treatments of muscle diseases have demonstrated efficacy in animal models. Efficient 

testing of these promising interventions in humans are necessary for the development of effective 

treatments for various muscle diseases. 

Broad areas of potential research directions include: 

• Developing plans for clinical trials based on strong, reproducible data from animal 

studies or previous studies in humans; 

• Conducting first-in-human studies to demonstrate safety and proof of concept needed to 

launch efficacy trials; 

• Conducting trials that test drugs, biologics, cell or gene therapies, molecular therapies, 

exercise regimens, or biomechanical or behavioral interventions that advance muscledisease treatments; 

• Evaluating potential additive or synergistic effects among interventions that have 

demonstrated efficacy; 

• Applying data from natural history, biomarker, and genetic modifier studies to inform 

more efficient and effective trial designs and increase the likelihood of trials reaching 

clear conclusions while minimizing the required number of research participants; 

• Designing clinical trials with outcome measures capable of following patients over the 

course of a disease so that both ambulatory and nonambulatory patients can be included 

in the trial; 

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• Promoting interactions with patients, families, and caregivers to develop strategies to 

lessen the burden of study participation on patients and family members and focus on 

outcomes most important to patients; 

• Standardizing outcome measures to allow for treatment comparisons addressed in 

different studies; 

• Encouraging the participation of diverse populations in muscle research; 

• Developing and testing specialized exercise “prescriptions” to maintain function, restore 

health, or improve quality of life; 

• Pursuing pharmacogenomic testing strategies that will allow personalized care with 

optimal treatment regimens; and 

• Conducting trials with behavioral interventions that address health services outcomes and 

daily living issues in people with muscle diseases. 

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Advancing and Accelerating Joint Biology, Diseases, and 

Orthopaedics Research 

NIAMS Joint Biology, Diseases, and Orthopaedics programs fund a broad spectrum of basic, 

translational, and clinical research centered on the interplay among the body’s muscles, bones, 

and connective tissues. These programs include research on the biology, structure, and function 

of joints and surrounding tissues and the application of this knowledge to a variety of diseases 

and conditions. Other programs fund tissue engineering and regenerative medicine to facilitate 

repair of damage caused by trauma to otherwise healthy tissue; molecular biology to understand 

the mechanisms of joint tissue formation and defects thereof; imaging to improve diagnosis and 

treatment of bone and joint disorders; and clinical research focused on treatment and prevention 

of acute and chronic bone and joint injuries and orthopaedic conditions, including 

musculoskeletal pain. Other sections of this plan address basic, translational, and clinical 

research interests related to bone, muscle, and rheumatic diseases. 

Biology, structure, and function 

Understanding the basic biology of joints and associated tissues is critical for the development of 

future basic and translational research studies. The complex interactions among the cells and 

tissues help define the physiological differences between healthy and diseased states. 

Molecular and cellular biology of joint/orthopaedic tissues 

A complex series of biochemical pathways and cellular interactions underlie the physiology of 

healthy, damaged, and diseased musculoskeletal tissues. Understanding the process by which a 

multicellular organism develops from its early, immature form into a fully mature form may 

deepen knowledge of disease mechanisms, regeneration strategies, therapeutic targets, and 

treatment design. Likewise, understanding the behavior of mature cells in their own environment 

is critical for developing cell-based strategies to repair or regenerate musculoskeletal tissues. 

Insights into how biological, chemical, and mechanical conditions affect cell behavior, as well as 

the microenvironment and the tissues from which those cells originate, will facilitate progress in 

this area. Since tissues do not exist in a vacuum, improved understanding of tissue crosstalk in 

development of and response to mechanical stress, as well as integrated physiology, provides a 

basis for translational and clinical studies. 

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Broad areas of potential research directions include: 

Development, maintenance, and degeneration of tissues 

• Characterizing molecules and signaling pathways that control cellular activities (e.g., 

stem cell renewal, pluripotency, and differentiation) essential for development and 

maintenance of relevant tissues (e.g., articular cartilage, growth plate, meniscus, 

ligament, tendon, and intervertebral disc), and for the development of tissue 

interfaces; 

• Elucidating the effect of mechanical factors on cell signaling in development of joint 

tissues and in disease; 

• Investigating the role of specific cell populations (e.g., tendon and meniscus 

progenitor cells, synoviocytes) and mechanisms of transdifferentiation in tissue 

development and repair; 

• Examining influences of various connective tissue components during normal joint 

maintenance and repair or during joint deterioration caused by disease; 

• Examining crosstalk and signaling among tissues involved in the formation and 

maintenance of joints (e.g., crosstalk between bone and connective tissue; immune 

response to mechanical stress or damage); 

• Investigating the origins and mechanisms of joint degeneration; and 

• Exploring synergies among therapeutic approaches that could yield improvements in 

the health and function of bone and connective tissue. 

Articular cartilage and chondrocyte biology 

• Characterizing interactions between cartilage matrix proteins; 

• Studying mechanisms of cartilage matrix maintenance and attrition, including 

glycation and other post-translational protein modifications; 

• Elucidating factors that contribute to chondrocyte cell death or chondrocyte 

proliferation under normal or pathologic conditions; 

• Investigating structure and function of the bone-cartilage interface; 

• Studying the role of mechanical stimuli on the formation, maintenance, and 

destruction of extracellular matrices; and 

• Exploring robust, minimally invasive, and minimally destructive approaches to 

imaging and cell tracing in articular cartilage and in the developing growth plate. 

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Tendons, ligaments, and menisci 

• Assessing effects of mechanical loading on the structural organization of menisci, 

tendons, and ligaments; 

• Exploring the structural organization and biogenesis of tendons, ligaments, and 

menisci, and their interfaces with muscle and bone: mechanisms underlying enthesis 

formation may be relevant to processes involved in joint degeneration; 

• Identifying differences that contribute to improved healing of lateral meniscal damage 

or that inhibit repair of damage to the medial side; 

• Studying mechanisms of tendinopathy to identify biomarkers and therapeutic targets; 

and 

• Developing cell-based therapies for tendons, ligaments, and menisci. 

Research needs and opportunities related to innovative treatments for enthesis repair were 

discussed in greater detail at a 2017 NIAMS roundtable discussion. 

Genomics and epigenomics 

• Characterizing gene networks responsible for specification of articular cartilage and 

for growth plate development; 

• Determining how mutations in individual cartilage matrix proteins affect chondrocyte 

behaviors and overall tissue structure and function; 

• Exploring possible roles of epigenetic mechanisms in the differential onset and 

progression of joint and orthopaedic diseases; 

• Studying mechanisms by which mutations, both coding and noncoding, and 

epigenetic differences contribute to joint and orthopaedic diseases; 

• Determining how intracellular and extracellular noncoding RNAs influence cell 

behavior in healthy and diseased or injured tissues; 

• Exploring genetic biomarkers or predictors of disease; and 

• Investigating the effects of exosomal signaling and tissue crosstalk on gene 

expression, including resultant effects on the function of articular cartilage and related 

tissues. 

Pathogenesis of osteoarthritis 

Osteoarthritis (OA), the most common degenerative joint disease, affects not only articular 

cartilage lining bone surfaces, but also components such as subchondral bone, menisci, 

ligaments, capsule, synovial membrane, and periarticular muscles. Excessive, debilitating 

deterioration of joint tissues is a hallmark of OA, regardless of whether it is caused by an 

inherited mutation, a developmental or posttraumatic joint instability, a failure of the 

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neuromuscular system to protect against repetitive loading, or metabolic events that cause 

excessive joint remodeling. Studies of the cellular and biomechanical factors responsible for OA 

onset and progression or promotion of healing and repair will likely require multidisciplinary 

research teams. 

Broad areas of potential research directions include: 

Influence of biomechanics and injury 

• Understanding the pathogenesis of post-traumatic OA (PTOA), including determining 

biomechanical factors (including gait) and biochemical pathways that influence 

initiation of joint changes associated with early OA, the progression of these changes 

to severe, late-stage OA, and joint deterioration/healing in response to acute injury; 

• Developing and validating alternative models (such as in vitro human tissue models 

and/or preclinical large animals) that accurately recapitulate disease onset and 

progression and limit confounding effects; 

• Investigating molecular signals that link mechanical loading with gene expression and 

the effects of that signaling; 

• Understanding basic biomechanical effects and related biochemical changes from 

obesity that lead to or exacerbate the development of OA in children and adults; and 

• Understanding the interaction among tissues surrounding joints, including cartilage, 

bone, muscle, tendon, and ligament. 

Inflammation 

• Further elucidating mechanisms in which nutrients and inflammatory signals are 

transported among the extracellular matrix, synovial compartment, and bone marrow; 

• Defining the relationship between inflammatory signals and biological responses in 

joints, subchondral bone, and synovial tissue; 

• Identifying signaling pathways triggered by joint inflammation, pathway origins, and 

their roles in joint degeneration; 

• Distinguishing between inflammatory pathways and factors that are involved after 

acute injury and during chronic disease; and 

• Studying the role of pro-inflammatory molecules, including the advanced glycation 

end products associated with obesity and diabetes, in joint degradation. 

Research needs and opportunities related to inflammation’s role in OA were discussed in greater 

detail at a prior NIAMS roundtable discussion. 

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Pain 

• Studying the genetic, molecular, biochemical, and immunological pathways that give 

rise to painful osteoarthritic joints; 

• Studying pain pathways activated during OA-induced mechanical stresses on joints; 

and 

• Studying the bidirectional interaction between joint damage and pain mechanisms, 

including biopsychosocial mechanisms, and investigating discordance between 

structural damage and pain severity: structural abnormalities are ubiquitous as people 

age, but pain is not. 

Genetic factors 

• Defining the role of cellular aging and aging-associated epigenetic changes on OA 

onset and progression; 

• Defining the role of epigenetic involvement of histone modification, DNA 

methylation, and tissue metabolism in pathogenesis of OA; 

• Identifying and investigating genetically defined subsets of OA; 

• Investigating early changes that occur in people with OA who advance to total joint 

replacement; 

• Adapting existing cohorts to genetic studies; 

• Determining contributions of gene-gene and gene-environment interactions to overall 

genetic influence on OA susceptibility; and 

• Using genetically modified animals and genomic analysis tools to understand the 

genetic components (including noncoding variation) involved in joint degeneration 

and to develop approaches for treating and preventing disease. 

Models for studying injuries and treatments 

Although small animals, such as mice, have their utilities in biomedical research, their biological 

relevance for understanding adult human health is sometimes less robust. More research is 

needed to understand the parallels between small and large animal models. Some large animals 

(e.g., equines, certain breeds of canines) are predisposed to develop musculoskeletal conditions. 

How do large animal models compare with small animal models that also model risk for 

musculoskeletal disorders (e.g., guinea pigs)? How do results vary between male and female 

animals and among animals at different life stages, and what do these differences teach us about 

human physiology and treatment responses? Is it possible to agree on a single large-animal 

model to parallel research that has been conducted in mice? 

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Broad areas of potential research directions include: 

• Developing well-characterized, age-appropriate animal models to study OA; 

• Developing standardized protocols for behavioral and biomechanical assessment needed 

to accurately phenotype animal models; 

• Developing and testing models that more closely resemble how people behave after 

injury: many experiments are designed such that interventions are begun soon after injury 

but people often wait to seek treatment; 

• Studying the local joint environment “post-injury” to identify approaches to protect 

tissues from damage and to promote tissue repair; and 

• Examining long-term outcomes of anterior cruciate ligament repair in large animals. 

Regenerative medicine 

Regenerative medicine is an area of science that seeks to develop new approaches for treating 

and even curing a variety of musculoskeletal injuries and diseases. It includes using stem cells 

and other technologies—such as engineered biomaterials and gene editing—to repair or replace 

damaged or aged cells, tissues, or organs, and aims to restore tissue/organ structure and function 

by tissue engineering and gene, cell, and pharmacological treatments. Multi- or interdisciplinary 

and collaborative research efforts involving both the life and physical sciences play key roles in 

moving this field forward. 

Some of broad directions in regenerative medicine include the following topics. 

Multi- or interdisciplinary research teams 

• Developing multi- or interdisciplinary research teams with expertise in the life and 

physical sciences (e.g., developmental biologists, immunologists working with tissue 

engineers) and promoting translational research; and 

• Encouraging cross-disciplinary discussions on broad issues, such as common standards, 

and providing opportunities for cross-training and education for emerging scientists. 

Basic biology 

• Understanding/controlling how stem cells differentiate, proliferate, and respond to 

physical stimuli in vitro and in vivo for the repair and regeneration of musculoskeletal 

tissues, including bone, cartilage, ligaments, menisci, tendons, and intervertebral discs; 

• Reactivating developmental pathways of organogenesis—how cells self-assemble into 

complex musculoskeletal tissues in vitro and in vivo; 

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• Understanding the role of inflammation, senescent cells, and changes in immune systems 

on musculoskeletal tissue development, injury, repair, and regeneration; and 

• Decoding how musculoskeletal tissues trigger and/or respond to vascularization, 

innervation, and immune signals. 

Biological therapy development 

• Designing and testing methods to deliver molecular, cellular, or gene-based therapies for 

repair of musculoskeletal tissues, and for joint disease treatment and prevention: of 

interest are in vivo strategies to deliver cells, genes, or biomolecules; 

• Developing methods for site-specific, endogenous gene- and cell-modulation to facilitate 

integration of engineered tissues; 

• Accelerating translation of cell-, gene-, and tissue engineering-based strategies into 

clinical testing by conducting preclinical studies in large animals; 

• Comparing and standardizing cell sources to identify promising approaches for advancing 

tissue engineering and regenerative medicine beyond the laboratory and into the clinic 

(e.g., adult stem cells from muscle, adipose tissue, or bone marrow versus differentiated 

cells such as chondrocytes; adult stem cells versus embryonic or iPS cells); 

• Developing strategies to recruit and direct endogenous progenitor or stem cells for 

regeneration; 

• Investigating the influence of stem and progenitor cells on inflammatory and immune 

responses and their effects on musculoskeletal tissue repair and regeneration; and 

• Expanding testing in preclinical models such as in large animal models for bench-tobedside translation of regenerative medicine research. 

Scaffolds and biomaterials for tissue engineering 

Successful tissue engineering strategies require biomaterials and scaffolds that support structural 

and functional development and maintenance of regenerated or repaired musculoskeletal tissues. 

Studying the biology of tissue development and organization often informs the design of optimal 

biomaterials and scaffolds. Such materials could be used when regenerating tissues in vitro for 

subsequent implantation in vivo, as well as in direct in vivo tissue regeneration and repair. 

Material development 

• Designing biomaterials and scaffolds that direct the growth, differentiation, and 

organization of cells by providing appropriate physical, chemical, and mechanical 

cues to form functional musculoskeletal tissues that mimic natural tissues’ 

biomechanical properties; 

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• Exploring innovative uses of the natural extracellular matrix as biomaterials or 

scaffolds to provide structural and mechanical properties appropriate for functional 

musculoskeletal tissues, and developing biomaterials that mimic or produce 

functionally superior scaffolds; and 

• Testing effects of biomaterials and scaffolds on the host immune system and 

inflammatory responses. 

Validation 

• Defining functional outcome measures to evaluate tissue-engineered products; and 

• Standardizing and comparing biomaterials and scaffolds to identify those with the 

most promise for transition from laboratory to clinic. 

Enabling technologies 

Methods and models 

• Developing and testing minimally or noninvasive methods and devices to monitor 

engineered tissues, track cell fate, and deliver scaffolds in situ; 

• Developing methods to control responses and interactions between cells and their 

local environments; 

• Finding new methods to sterilize and preserve natural and synthetic materials and 

scaffolds to render them suitable for implantation; 

• Facilitating the standardization of tissue culture reagents and protocols, safety 

procedures, outcome measures, testing and validation of animal models, and 

evaluation techniques; and 

• Developing 3D in vitro human musculoskeletal tissue model systems to study human 

physiology and disease pathogenesis, as well as for drug discovery and toxicity 

studies or for testing a proposed intervention’s feasibility, function, and safety in 

preparation for in vivo studies. Such research on the development of tissueengineered, cell-based models would reduce the cost of using animal models and 

lessen the scientific community’s need to study animal models of human disease. 

Imaging and computational tools for regenerative medicine 

• Developing real-time, minimally or noninvasive imaging modalities for in vivo 

monitoring of cell proliferation, differentiation, survival, migration, and integration; 

• Developing real-time, minimally or noninvasive imaging modalities to monitor 

tissue-function repair and integration processes in vivo; 

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• Developing noninvasive imaging methods to measure functional capacity of tissue in 

small and large animal models and in humans; and 

• Developing computational models to facilitate experimental design and effectively 

predict outcomes. 

Functional integration 

Research on the integration of regenerated or engineered tissues within a host organism must 

reflect the complex physiological interactions that occur across multiple tissue types. Such 

systemic interactions include biological signaling processes, vascularization, innervation, and 

influences from the innate and adaptive immune systems. Preservation of structural and 

mechanical function, host and graft survival, and safety are also important. 

In addition to research topics identified under Enabling technologies, above, broad research 

directions include: 

• Studying the relationship between regenerative medicine and rehabilitation; 

• Studying the impact of inflammation and immune responses on regenerative processes; 

• Developing strategies to integrate engineered tissues with the host while reducing adverse 

effects (e.g., immunogenicity, toxicity) and considering ongoing disease progression; and 

• Developing, validating, and standardizing functional outcome measures that assess a 

treatment’s effectiveness objectively. 

Preclinical and translational research into joint replacements 

Implants such as those used in total hip and knee replacements have been shown to be effective 

tools to treat end-stage arthritis that has not responded to nonoperative treatment. These implants 

improve an individual’s functionality and quality of life. If a joint implant fails, however, an 

individual may require a second surgery that is not likely to be as successful as the initial 

procedure. The main cause of failure is osteolysis (disappearance of bone surrounding an implant 

caused by a reaction to microscopic particles from an implant). Numerous research opportunities 

exist to develop improved biomaterials, tools to better assess implant wear, and increased 

knowledge of osteolysis biology and pathophysiology. Investigators are encouraged to avail 

themselves of data from registries of implant failures/retrievals, when appropriate. 

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Broad areas of potential research directions include: 

Improved materials and designs 

• Exploring the chemistry of interactions between biologic lubricants and implant-bearing 

surfaces; 

• Improving strength and fatigue resistance of implant materials without compromising 

wear and oxidation resistance; 

• Developing new materials and modifying surfaces of existing materials to lessen wear 

and reduce failure rates; 

• Developing materials/surface modifications that facilitate healing by stimulating implant 

integration and preventing infection; 

• Using data-driven design approaches to improve implant durability and performance; and 

• Developing unique 3D-printed orthopaedic implant materials. 

Tools for improved implant design and testing 

• Developing methods to better assess metal-on-metal implant wear, particularly in people 

with well-functioning implants who do not exhibit symptoms of elevated blood levels of 

metal ions; 

• Measuring wear in total knee and hip replacements (e.g., automated image recognition 

software is one possible tool for such studies); 

• Designing models to predict functional performance or possible causes of implant failure 

(e.g., joint instability, excessive wear, fracture, implant loosening); 

• Standardizing mechanical-testing strategies to assess performance and fracture resistance 

of new formulations; and 

• Studying efficacy of CT and MRI scanning in implant modeling (including 3D printing) 

and for assessing the extent of implant osteolysis. 

Implant deterioration and failure 

• Analyzing biologic responses (including innate and adaptive immune responses) to 

implant-wear particles and their role in implant failure; 

• Pursuing clinical and histopathological studies to better understand, diagnose, and treat 

metal hypersensitivity; 

• Identifying features of wear debris most critical in determining biological responses to 

implant-wear particles: detailed mechanistic studies of pathogenesis of periprosthetic 

osteolysis and implant loosening in different joints (e.g., hip, knee, and spine) may be 

useful; 

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• Explaining and quantifying features of third-body wear (implant debris that becomes 

trapped between two implant surfaces) and designing preventive strategies to counter it; 

• Understanding effects of mechanical factors (e.g., motion and pressure) on implant wear 

and loosening; 

• Elucidating effects of stress shielding on bony structures (e.g., the acetabulum) that 

support implants; 

• Identifying biological and implant characteristics that predispose some people to develop 

chronic or recurrent bone infections after joint replacement surgery; and 

• Using genome-wide analyses and other high-throughput genetic approaches to 

understand genetic risk factors for, and their relevance to, osteolysis. 

Biochemical and imaging biomarkers and computational modeling 

Many musculoskeletal diseases are chronic and have long variable clinical courses. These 

conditions often take decades to develop and can be difficult to characterize. Disease progression 

and treatment responses are often determined through measurement of biochemical factors in 

blood or body fluids or through analyses of genetic biomarkers from tissues or peripheral blood 

cells. Broad, innovative use of imaging techniques, in combination with measurements of 

biochemical markers, could also allow early identification of disease onset, predict disease 

progression, facilitate surgical decision making, and enable direct monitoring of responses to 

tissue repair and therapeutic interventions. 

For many musculoskeletal conditions, responses to therapies are difficult to determine. 

Researchers are beginning to believe that, as with many disorders, a battery of several 

biomarkers may be more useful than a single marker for assessing these conditions. In addition, 

when many different variables are collected, deducing connections among variables may require 

the aid of machine learning algorithms. These algorithms may result in computational models 

that can be used to subphenotype patients to improve diagnosis and treatment of musculoskeletal 

diseases. Moreover, leveraging the power of machine learning and automation of morphological 

grading of the tissues in the joints would enable the analysis of large sample sizes and assist the 

radiologist/clinician in the grading of images in a relatively short amount of time at significantly 

reduced cost. The box below describes an NIH effort to create a public resource to validate 

imaging and biochemical biomarkers for OA. 

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The Osteoarthritis Initiative (OAI): A Public-Private Partnership to Advance Biomarker 

Discovery 

OA is the most common type of arthritis. It occurs when the tissue that covers the ends of bones 

in a joint is damaged, which allows the bones to rub together leading to pain, swelling, and loss 

of motion. A limited number of therapies exist for OA treatment. One barrier to the development 

of drugs that interrupt the underlying disease processes leading to OA is a lack of objective and 

measurable standards for disease progression for these new drugs. To overcome this problem, 

NIAMS, along with the National Institute on Aging (NIA), led the development of the 

Osteoarthritis Initiative (OAI), a nationwide, multicenter observational study to follow people 

who either have or are at risk for developing knee OA. This public-private partnership began 

more than a decade ago to gather and catalog longitudinal findings from a cohort of nearly 5,000 

people with OA and healthy individuals. 

All participant visits (baseline through 8 years follow-up) have been completed, which makes the 

OAI one of the largest and perhaps most important datasets in the history of OA research. The 

dataset contains clinical, genomic, patient-reported, and functional data; biological specimens; 

and X-ray and MRI images. The data are available free of charge at https://oai.nih.gov. In 

addition, genomic data from the ancillary Genetic Components of Knee Osteoarthritis (GeCKO) 

study, a genome-wide association study on the entire OAI cohort is available at the NCBI dbGaP 

website. Investigators can use this unique repository to track the natural history of knee OA 

across the complete spectrum of disease. 

As NIAMS looks to FYs 2020-2024, extramural researchers are encouraged to examine OAI 

data to develop hypotheses about possible OA biomarkers of disease onset and progression, test 

their theories, describe the natural history of OA, and investigate factors that influence disease 

development and severity. These comprehensive datasets can be used to identify potential 

disease biomarkers and develop tools for measuring clinically meaningful improvements. The 

initiative also provides excellent training and research opportunities for early-stage investigators 

with limited funding to leverage this existing dataset and develop and test research hypotheses. 

In addition, OAI data serve as a novel resource for investigators with computational and machine 

learning expertise in other fields to apply big data methodologies to biomedical research. 

For further information: https://www.niams.nih.gov/grants-funding/fundedresearch/osteoarthritis-initiative. 

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In addition to opportunities regarding biomarkers and imaging methods described under 

Preclinical and translational research into joint replacements above, broad areas of potential 

research directions include: 

Biomarker identification and validation 

• Broadening biomarker research to address genetic markers of disease or markers that may 

predispose individuals to a heightened risk of disease progression, worsening, and 

severity, or research that predicts treatment response via biomarkers; 

• Conducting basic exploratory studies to identify candidate biomarkers at molecular and 

cellular levels to facilitate early detection of pre-OA; 

• Developing and applying new technologies to discover biomarkers of disease onset, 

progression, and treatment response; 

• Identifying post-injury joint changes that cause or predict OA; 

• Identifying biomarkers useful for predicting overall outcomes or those in specific subsets 

of people: of particular interest is the use of existing repositories and databases to validate 

biochemical and structural changes associated with OA onset and progression; 

• Combining markers of cartilage and bone catabolic activity, imaging markers, 

proinflammatory cytokines, and gait-analysis data to determine optimal timing of joint 

replacement in OA and to identify people at risk of implant failure; 

• Studying noninvasive biomarkers to facilitate early diagnosis and monitor treatment of 

musculoskeletal infections, including those surrounding implanted devices; and 

• Developing in vivo molecular imaging technologies to facilitate the use of biomarkers to 

distinguish between diseased and healthy tissue (e.g., biomarkers and intra-operative 

molecular imaging methods to better assess joint tissues). 

Resource development and application 

• Implementing novel imaging modalities in preclinical and clinical studies; 

• Applying existing and newly developed imaging technologies (for both acquisition and 

analysis) when studying disease and identifying possible imaging biomarkers associated 

with disease onset and progression; 

• Employing existing resources, such as databases and clinical cohorts, to transition 

promising biomarkers from laboratory to clinic through application of state-of-the-art 

statistical, analytical, and computational methods; 

• Developing rigorous patient-based musculoskeletal computational models to assist with 

treatment planning and predict outcomes; and 

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• Developing supervised or unsupervised deep machine learning approaches for image 

processing, analyzing complex biostructural, biomechanical and functional models, 

enabling reliable and standardized disease screening, detection, and automatic analysis. 

Clinical research 

Characterization of disease in the context of clinical studies may enable researchers and health 

care providers to distinguish between disease subtypes that produce similar endpoints (e.g., OA, 

connective tissue injuries). As investigators consider clinical studies of musculoskeletal and 

orthopaedic conditions and trials of potential diagnostic strategies and treatments related to the 

broad areas described below, they are encouraged to consider the following issues: 

• The role of personalized medicine in maintaining or restoring musculoskeletal health; 

• Assessment of effectiveness, as well as efficacy, for reducing pain and improving 

function; 

• The importance of measuring a combination of outcomes so that results are meaningful to 

individuals and health care providers; 

• Development and validation of patient-reported outcomes, including health-related 

quality-of-life measures, for different orthopaedic procedures; 

• The use of registries, electronic medical records, and large databases to inform clinical 

studies; 

• The development and use of unique clinical trial designs (e.g., pragmatic, adaptive); 

• The importance of improved understanding of the role of psychological and social factors 

in musculoskeletal health; and 

• Integration of social media and technology into clinical studies to improve research 

efficiency. 

Conditions, diseases, and disorders 

Childhood musculoskeletal conditions 

The cost of childhood musculoskeletal conditions is enormous. Although some conditions can be 

treated effectively, resulting in full restoration of an active life, others can result in early death or 

progressive problems into adulthood. Still others present lifelong challenges for the affected 

individual and his or her family. 

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Prevention of childhood injury is addressed under Fractures and other types of musculoskeletal 

trauma, below. Other broad areas of potential research directions include: 

• Developing physiological interventions to correct skeletal deformities and neuromuscular 

disorders, including muscular dystrophies; and 

• Studying musculoskeletal implications and complications of rheumatic diseases in 

children (e.g., growth delay, osteoporosis, avascular necrosis, scoliosis). 

Osteoarthritis 

OA is by far the most common type of arthritis, which affects an estimated 27 million Americans 

age 25 years and older. Although this prevalence is high, it is expected to increase even further 

with the increasing prevalence of obesity and the aging population. OA can affect quality of life 

and the ability to work and perform basic activities of daily living. Healthy People 2020 includes 

several objectives related to improved overall health and functioning of people who have 

arthritis. Current therapeutic regimens for OA are only partially effective and often have 

associated toxicities, and there are no disease-modifying drugs approved by the regulatory 

agencies at present. Further research is needed to develop effective therapies. Also see Joint 

replacement and Behavioral and psychosocial research sections for more information. 

Broad areas of potential research directions related to risk factors include: 

• Defining and stratifying OA risk factors, both modifiable and nonmodifiable, for 

incidence, morbidity, and mortality in individuals and in populations (nonmodifiable risk 

factors are age, sex, genetics and inherited traits; modifiable risk factors include weight 

and obesity, previous joint injury, diet, physical activity, coincident pathology of other 

tissues and organs, and medication use); 

• Determining effects of changes in modifiable risk factors on OA onset and progression; 

• Emphasizing disease prevention by developing or modifying strategies, including 

behavioral and rehabilitative approaches, to avoid and prevent the development of OA 

after joint injury and to reduce the disability and functional limitations associated with 

OA onset and progression; 

• Taking advantage of web-based and mobile technology to prevent poor outcomes after 

joint replacement surgery; 

• Modulating triggers to prevent disease flares and prevent acute to chronic pain 

transitions; 

• Subphenotyping OA patients, identifying responders and nonresponders to treatment to 

match a patient’s phenotype to an appropriate effective treatment; 

• Exploring rehabilitation and physical therapy strategies to reduce risk for impairment 

from OA progression; 

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• Identifying and characterizing agents and methods to decrease disability and pain from 

OA-related tissue degeneration; 

• Investigating strategies to prevent or reverse structural modifications of diseased joints 

and identifying new targets/developing corresponding therapeutic agents; 

• Identifying and developing solutions to barriers and enablers to enhance sustainability 

and adherence to exercise and weight loss interventions; 

• Comparing the effectiveness of treatment programs to improve adherence and outcomes 

for patients; 

• Identifying novel targets, developing novel drugs or repurposing existing drugs as 

DMOADs (disease-modifying osteoarthritis dugs); 

• Pursuing innovative treatments (such as biologics and stem cells) to slow or prevent joint 

degeneration, and developing novel drug delivery approaches; 

• Adopting modern clinical trial designs, for example, adaptive and pragmatic trials, to 

devise more efficient, less costly strategies for answering multiple questions about 

treatment effects and patient responses; and 

• Establishing innovative approaches to using patient-reported outcome scores in decision 

making. 

Joint replacement 

As described in Preclinical and translational research into joint replacements, above, implants 

for total hip and knee replacements are effective treatments for people with end-stage arthritis 

and for other surgical needs. Although infection at the site of a total joint replacement is rare, it 

can be devastating and require lengthy hospitalization. Other complications include implant 

loosening or failure, both of which require additional surgeries that are less likely to be as 

successful as the initial joint replacement. In addition to preclinical research examples noted in 

Preclinical and translational research into joint replacements and Biochemical and imaging 

biomarkers and computational modeling above, broad areas of potential patient-oriented 

research directions include: 

Outcomes: 

• Analyzing outcomes of revision total knee and hip replacements (such studies could 

be useful for identifying grafting techniques that lead to well-fixed implants, defining 

the roles of bone and synthetic graft materials, and quantifying graft incorporation 

and bone resorption); 

• Developing and implementing strategies to prevent implant-related musculoskeletal 

infections, their transition to chronic infections, and their post-treatment recurrence; 

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• Investigating effects of anabolic agents administered postoperatively to see whether 

they can significantly increase implant osteointegration and decrease subsequent 

loosening; 

• Testing long-term biocompatibility and wear properties of alternative-bearing 

surfaces; 

• Standardizing criteria for determining therapeutic effects of nonsurgical interventions 

(such as drugs or rehabilitation strategies) to prevent or treat implant osteolysis (this 

will enable comparison of interventions across different studies); and 

• Developing and adapting patient-reported outcomes for different orthopaedic joints. 

Techniques and timing: 

• Assessing impact of small-incision, minimally invasive surgical approaches and 

robotic surgery on functional outcomes, complications, and revision rates; 

• Developing and validating effective pre- and post-operative rehabilitation strategies, 

especially for hip and knee replacement; 

• Improving links between implant-improved performance and surgical/patient 

characteristics; and 

• Studying the clinical and economic impact of earlier diagnosis of implant osteolysis. 

Spinal disorders 

Many spinal disorders are common, costly, and potentially disabling. Low back pain affects 

millions of people globally and exerts an enormous socioeconomic impact. A frequent cause of 

disability, low back pain causes employees to lose many days of work each year. Its costs to 

society, and opportunities to reduce those costs, earned its position as a Healthy People 2020 

objective, “Reduce activity limitation due to chronic back conditions.” Although low back pain 

is an important public health issue, little is known about its causes. A considerable investment in 

a study of surgical and nonsurgical therapies for common causes of low back pain has yielded 

important results. However, much remains to be discovered about strategies to improve the lives 

of people affected by back pain or related conditions. To facilitate research on chronic low back 

pain, an NIH task force developed research standards that include defining chronic low back 

pain, assessing its impact on people’s lives, identifying the minimum dataset that should be 

collected in chronic low back pain research, and defining optimal outcomes to evaluate treatment 

effectiveness. Recently, NIAMS established the NIH Back Pain Consortium Research Program 

(see Musculoskeletal pain below), a patient-centric program to promote understanding of the 

causes of and treatments for chronic low back pain. 

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Broad areas of potential research directions include: 

• Developing and evaluating new treatment methods and technologies for degenerative disc 

disease, including use of an artificial disc and nucleus and use of regenerative medicine 

techniques to reverse disc degeneration; 

• Assessing basic/clinical biological mechanisms associated with spinal disorders and their 

related pain syndromes; 

• Acute and chronic back pain (in regions spanning the cervical, thoracic, and lumbosacral 

spine); 

• Pursuing clinical studies to address management of spinal disorders for which consensus 

regarding preferred treatment is lacking; 

• Studying efficacy and effectiveness of current and emerging technologies for treating 

spinal disorders; and 

• Facilitating mechanistic and outcomes research across disciplines through the continued 

development and use of common data elements and terminology. 

Fractures and other types of musculoskeletal trauma 

In addition to treatment-associated health care expenditures from fractures and other types of 

musculoskeletal trauma, these conditions cost billions of dollars in terms of lost employment. 

Traumatic musculoskeletal injuries can lead to lifelong disability. Trauma is one of the leading 

causes of death after the first year of life. Treatment of people with fractures in conjunction with 

trauma to other organ systems (e.g., traumatic brain injury) is a challenge in musculoskeletal 

care. After-injury prevention methods to reduce complications, disability, and mortality are 

paramount. Further refinement of operative and nonoperative techniques and rehabilitation after 

fractures or skeletal trauma will improve patient outcomes, enhance the lives of patients and their 

caregivers, and facilitate return to the workforce. 

Broad areas of potential research directions include: 

Prevention: 

• Elucidating mechanical forces that contribute to or cause joint injuries (e.g., ACL 

tears, herniated discs) and understanding the consequences of cumulative trauma 

disorders of soft tissues (such studies could be useful for preventing injuries and 

developing protective devices for preventing these injuries); 

• Defining the role personalized medicine can play in maintaining bone and joint 

health; 

• Developing injury prevention programs that are cost effective, easily applicable, and 

readily disseminated to diverse populations; 

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• Preventing childhood/adolescent injuries (including sports related injuries); and 

• Assessing effectiveness of strategies for preventing soft tissue injuries in children and 

adults. 

Management: 

• Further establishing outcomes and cost effectiveness of treatments for specific 

fractures and other musculoskeletal injuries, including those of ligaments, tendons, 

and other musculoskeletal soft tissues. 

• Developing and validating measures that better assess and aid fracture healing; 

• Testing methods to diagnose and treat injuries to and around growth plates to prevent 

growth disturbances; 

• Improving strategies for repairing fractures in older people; 

• Refining prevention, diagnostic, and treatment strategies related to chronic or 

recurrent bone infection following limb trauma; 

• Enhancing fracture healing through bone grafts and other implant materials, including 

the use of growth factors; 

• Developing methods to repair damage to cartilage, connective tissue, and 

fibrocartilaginous tissues (including menisci) related to fractures in the joint area; 

• Improving diagnostic methods and treatments of focal cartilage defects, subchondral 

bone changes, and other types of joint damage to prevent post-traumatic OA; 

• Optimizing methods of repairing or replacing damaged ligaments and menisci to 

reduce pain and dysfunction and to improve long-term outcomes; 

• Improving and developing strategies to diagnose and treat symptomatic rotator cuff 

tears; 

• Exploring the natural history of rotator cuff tears to understand why some are more 

symptomatic than others; and 

• Implementing strategies to standardize clinical studies of interventions that influence 

fracture and soft tissue healing, using both objective and subjective parameters. 

Trauma to multiple organ systems: 

• Enhancing strategies to recognize and treat combined injuries, especially as they 

relate to the timing and type of surgery in people subjected to multiple traumatic 

insults (e.g., those suffering fractures in addition to head injury, chest and/or 

abdominal injury, or shock). As with other research or clinical practice that involves 

multiple tissues and organ systems, work in this area will likely involve teams of 

investigators with expertise in multiple disciplines; and 

• Improving surgical strategies to correct injuries affecting multiple systems such as 

compartment syndromes and mangled extremities. 

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Sports medicine and fitness 

Fitness is associated with good health and a sense of well-being. Numerous studies have shown 

beneficial effects of exercise in disease prevention; yet one problematic feature of exercise is 

potential injury. Musculoskeletal soft tissues are vulnerable to injury and damage as the result of 

overuse and/or trauma. These injuries are often life-altering. 

In addition to examples noted under Osteoarthritis and Fractures and other types of 

musculoskeletal trauma above, broad areas of potential research directions include: 

Physical activity requirements 

• Acquiring better understanding of how particular fitness requirements vary by sex, 

age, and conditions that limit mobility (such knowledge is important for efforts to 

encourage physical fitness and promote health); and 

• Identifying markers of bone, cartilage, and muscle quality that could facilitate studies 

of which types of exercise are optimal for promoting musculoskeletal health. 

Injury prevention 

• Characterizing sex differences in ultra-high-performance sports as the groundwork 

for development of focused programs to prevent injuries and overuse disorders 

commonly seen in athletes (including repetitive motion disorders of the rotator cuff); 

and 

• Prevention of secondary injuries (in shoulder and ACL, including reinjury or 

contralateral injury). 

Treatment and rehabilitation 

• Applying physical medicine and rehabilitative strategies to soft tissue injuries to 

restore maximal function and enhance return to sport; 

• Determining types and levels of exercise effective for minimizing progression of 

specific diseases and promoting restoration of musculoskeletal function (such 

knowledge could translate into “exercise prescriptions”); 

• Developing musculoskeletal “prehabilitation” programs to improve functional 

outcomes after surgery; 

• Developing state-of-the-art technologies to aid in the diagnosis and treatment of 

musculoskeletal injuries (including wearable devices and ultrasound-guided 

interventions); and 

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• Developing and optimizing the clinical use of biologics (including stem cells, platelet

rich plasma, bone marrow, and fat cells) as treatments for musculoskeletal injuries.

Additional information on the use of biologics in clinical orthopaedics can be found

in the consensus report from an NIAMS-funded American Academy of Orthopaedic

Surgeons meeting in 2018.

Musculoskeletal pain 

Musculoskeletal pain takes many forms in children and adults. From acute and chronic back pain 

to tendonitis, myalgia, joint pain, stress fractures, and growing pains, there are many unmet 

needs. These include an improved understanding of the biological underpinnings of the origins of 

pain and discovery, development, and testing of new nonaddictive pain treatments. For example, 

more rigorous studies are needed to improve our understanding of the mechanisms of chronic 

low back pain, improve its diagnosis and treatment, and prevent its transition from acute to 

chronic status. To improve understanding of chronic low back pain, NIAMS developed the NIH 

Back Pain Consortium Research Program (BACPAC), part of the NIH HEAL initiative (Helping 

to End Addiction Long-termSM). This research program is a patient-centric translational research 

initiative that will address the need for effective and personalized therapies for chronic low back 

pain by probing the biomedical mechanisms in a biopsychosocial context using interdisciplinary 

methods and innovative technologies. 

Broad areas of potential research directions include: 

• Using advanced genetic, molecular, neurobiological, behavioral, and imaging techniques

to identify mechanisms, genetic and molecular pathways, and biological processes of

musculoskeletal pain;

• Exploring biopsychosocial mechanisms of pain, including sensory, cognitive, and

affective components of pain, and determining the relationship between tissue damage

and the experience of pain;

• Developing novel animal models that are highly relevant to human musculoskeletal pain

conditions;

• Developing novel technologies, including sensor-driven implantable devices and

wearable technologies, to target peripheral pain pathways, detect cellular and structural

changes of tissues and organs, and record patient functional outcomes;

• Defining and supporting best practices for pain management using nonpharmacological

and integrated therapies for specific musculoskeletal pain conditions;

• Examining different components and effectiveness of self-management strategies for

chronic pain; and

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• Advancing the development of new nonaddictive pain treatments by building mechanistic 

research centers, clinical trials networks, and pursuing public-private partnerships for 

data sharing. 

Behavioral and psychosocial research 

Behavioral and psychosocial factors are involved in the onset, course, and outcome of chronic 

diseases. These factors are central in the experience of symptoms (such as pain and fatigue), 

disease-related distress, and coping with chronic disease, disability, and to varying extents the 

effectiveness of prevention and treatment. Interdisciplinary research that integrates behavioral 

and biomedical sciences is likely to result in enhanced management of and reduced disability 

from chronic diseases and may shed light on complex mechanisms involved in pathogenesis. 

Broad areas of potential research directions include: 

• Assessing the willingness of individuals belonging to racial and ethnic subpopulations in 

the United States to undergo total joint replacement and developing strategies to ensure 

that all Americans who have severe OA can make the best possible decisions regarding 

their treatment; 

• Determining mechanisms and outcomes of behavioral therapies for treating chronic 

musculoskeletal conditions and injuries; 

• Developing and validating accurate and appropriate outcome measures for studying 

disability related to musculoskeletal conditions and injuries; 

• Clarifying the impact that psychological distress has on recovery after musculoskeletal 

trauma and designing strategies to prevent or reduce it; 

• Determining which outcomes of musculoskeletal diseases and procedures are influenced 

by modifiable attributes such as beliefs, attitudes, and psychological states and pursuing 

strategies to improve health; 

• Determining which behavioral interventions can be delivered by someone other than a 

physician without losing effectiveness; and 

• Exploring strategies to sustain behavioral interventions known to be effective for 

behavior modification leading to desired health outcomes (e.g., weight loss). 

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MANAGEMENT, SCIENTIFIC STEWARDSHIP, AND 

ACCOUNTABILITY 

Through responsible management and scientific stewardship NIAMS promotes exploration of a 

broad spectrum of highly meritorious research. Several of the Institute’s current activities related 

to management, stewardship, and accountability are described in the following sections. The 

Institute will continue to support and promote these activities over the next 5 years while looking 

for new opportunities to promote scientific stewardship and accountability. 

An important component of management at NIAMS is a planning and priority-setting process 

that incorporates input from the research community. NIAMS also considers assorted relevant 

data when making decisions about scientific programs and conducts quantitative or qualitative 

assessments of programs and research topics, as needed, to guide future activities. 

NIAMS also implements trans-NIH activities to enhance management, stewardship, and 

accountability. For example, these include efforts to reduce administrative burden on 

investigators, proactively manage risks that might impede the agency’s mission, and ensure that 

NIAMS-funded research is conducted with a high degree of scientific rigor and in accordance 

with ethical standards. 

NIAMS seeks to ensure the continuity and progress of research in its mission areas through 

training and career development programs for outstanding early-stage investigators and through 

dedicated funding for studies with the potential to positively shift scientific paradigms. The 

Institute fosters a vibrant research environment through investments in key research resources 

and facilitates access to those resources and data through partnerships with a wide array of public 

and private organizations in mission-relevant areas. 

Accountability for taxpayer funds is a key guiding principle of NIAMS activities. The Institute 

seeks to ensure integrity, accountability, and transparency in the grant award and administration 

processes. Program Officers and Grants Managers work closely together to accomplish this goal. 

One group is responsible for the fiscal and administrative management of a grant award and the 

other for the scientific and programmatic aspects. Staff work closely with awardees to ensure 

effective management and oversight, while also providing excellent customer service and 

guidance. 

Pre-award processes assure that established administrative, ethical, and financial requirements 

are met, including protection of human and animal subjects, monitoring of conflicts of interest, 

promoting data sharing, and requiring the responsible and ethical conduct of research. Postaward monitoring assures that projects are managed appropriately and that funds are being spent 

121 
 

 

 

 

 

 

 

 

in a prudent and effective way. Grant closeout procedures assure final progress and expenditures 

are reported and that results are available to the public. 

Further, the Institute is committed to supporting research that reflects the diversity of the Nation 

so that the results of NIAMS-funded research benefit all members of society. NIAMS also 

prioritizes outreach to the public and broad dissemination of research findings to encourage their 

implementation to improve health. 

Priority Setting 

Like the rest of NIH, the process of setting NIAMS’s research priorities balances opportunities 

presented by the best science, public health needs, and the unique ability of the Institute to 

address challenges in human health that would otherwise go unmet. NIAMS’s long-standing 

priority setting process is predicated on three activities: 

• Submission of investigator-initiated research applications; 

• Peer review to identify the most promising research projects; and 

• Stakeholder input on research gaps and opportunities. 

Going forward, NIAMS will continue to rely on these priority-setting activities and will seek out 

opportunities to enhance them. 

Submission of investigator-initiated research applications 

NIAMS believes that investigator-initiated research is a key part of efforts to improve the health 

of people who have rheumatic, musculoskeletal, and skin diseases. The term “investigatorinitiated” means that a researcher bases his or her grant proposal on any area of science that 

NIAMS supports instead of waiting for the Institute to publish a special funding opportunity 

announcement seeking applications on a specific topic. This has the dual advantages of 

positioning the Institute to receive the best, most interesting and promising ideas from the 

research community and of allowing investigators the creativity and freedom to explore the 

topics that they are most interested in and best poised to address. 

The NIAMS portfolio covers a broad and diverse spectrum of research and training 

responsibilities and NIAMS does not set aside particular pools of money for disease- and tissuespecific topics within its mission. This provides the Institute the flexibility to fund the most 

outstanding research grant applications regardless of scientific discipline and to fund as many as 

possible of the myriad needs and opportunities across the broad base of science within its 

mission. 

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Peer review to identify the most promising research projects 

The decision to fund an application is based on the assessment of scientific merit by a peer 

review group and on the relevance of the proposed work to the Institute’s scientific and health 

priorities. While the Institute Director ultimately is responsible for deciding which applications 

to fund, the assessments of expert scientists and lay representatives from around the country 

factor heavily into the decision-making process. 

Peer reviewers’ judgments of scientific merit are expressed in “priority scores” and in percentile 

rankings derived from these priority scores. At any point in a given fiscal year, budgetary 

projections are based on awarding funds to applications with rankings better than a certain 

percentile, sometimes referred to as the “payline.” However, applications that address topics of 

particular relevance to the Institute’s scientific and health priorities may be considered for 

awards even if their assigned scores and percentile rankings would not qualify for funding under 

the current payline. Normally, a small portion of each year’s budget is reserved for such 

“discretionary” or “select pay” awards. Projects to be funded on this basis are recommended by 

Institute staff or Advisory Council members. Applicants may not apply for select pay 

consideration. Final decisions are made by the Director, NIAMS, following staff discussion. 

Rarely, NIAMS receives an application that is within the Institute’s payline but is deemed to be 

of low program priority. In such instances, these cases are discussed in depth with members of 

the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council before the 

Institute Director makes a final funding decision. An application can be considered low priority 

for many reasons, including (but not limited to) redundancy with other projects or concerns 

about the ultimate relevance of the proposed study’s results or about the scientific premise. 

NIAMS publishes its funding plan for each fiscal year on an annual basis on the NIAMS 

website. 

Stakeholder input on gaps and opportunities 

NIAMS routinely invites input from the extramural scientific community and members of the 

broader public by issuing Requests for Information or through listening sessions with researchers 

and NIAMS Coalition members. Such activities have shaped this Strategic Plan and other 

NIAMS initiatives and programs, both large and small. 

NIAMS has a history of carefully considering input from the National Arthritis and 

Musculoskeletal and Skin Advisory Council before making significant changes to existing 

programs and often presents data-driven analyses to the Council when soliciting its input. Recent 

examples include the decision to change the eligibility criteria for the Supplements to Advance 

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Research (STAR) program (discussed below) and the Small Grant Program (R03). Council input 

also has shaped Institute policies regarding the clinical trial applications that it considers and the 

structure of the NIAMS Centers programs. 

Workforce Recruitment, Development, Retention, and Diversity 

Biomedical and behavioral research is a human endeavor and NIAMS is committed to keeping 

the scientific workforce pipeline strong and diverse. Through ongoing assessment of needs and 

opportunities, NIAMS has maintained a multidimensional approach to training and career 

development. Nurturing a healthy pipeline of biomedical researchers focused on the diseases and 

disorders that are included within the NIAMS mission is critical to advancing scientific progress. 

Many research questions important to the NIAMS mission will require multi- and 

interdisciplinary contributions and a thorough understanding of how to work within teams and 

across traditional scientific silos. NIAMS encourages investigators to design training experiences 

that include team science and multidisciplinary or interdisciplinary projects, as appropriate. In 

addition, NIAMS recognizes a need to incorporate additional areas of expertise, such as data 

science, biomedical engineering, clinical trial design, and patient engagement, to ensure the 

effective translation of scientific discoveries into health benefits. To meet these needs, NIAMS 

encourages new approaches to ensure individuals with nontraditional areas of expertise are 

represented in research teams. 

Going forward, NIAMS will continue to leverage existing and emerging programs and 

mechanisms to ensure there is a robust and diverse pipeline of researchers and clinician-scientists 

to carry the Institute’s mission forward. The Institute remains interested in developing 

partnerships with research and professional societies or patient organizations to encourage 

trainees and clinicians to enter the scientific research workforce or to maintain research efforts as 

investigators make critical career-stage transitions. 

Building and maintaining the workforce 

Attracting and maintaining a robust, diverse scientific workforce is critical to the NIAMS 

mission. The Institute participates in many trans-NIH programs to encourage and foster the 

development of early-stage investigators as they pursue research projects on arthritis, rheumatic 

diseases, musculoskeletal conditions, and skin diseases. Predoctoral fellows in Ph.D. or formal 

dual-degree programs, such as M.D./Ph.D. programs, and postdoctoral fellows may be eligible 

for individual Ruth L. Kirschstein National Research Service Awards (NRSAs). Universities and 

other eligible organizations can apply for institutional NRSAs that provide support for both 

predoctoral and postdoctoral trainees. 

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In addition to encouraging trainees to pursue research in NIAMS mission areas, the Institute 

employs several approaches to encourage clinicians to enter into or continue their research 

careers. A suite of mentored career development awards aid emerging clinician-scientists as they 

develop independent research careers by providing resources and protected time for research. For 

example, the NIH Mentored Clinical Scientist Research Development Award (K08) supports 

clinicians for an intensive experience in basic and translational research. In addition, the NIH 

Mentored Patient-Oriented Research Career Development Award (K23) is targeted to individuals 

with a clinical doctoral degree who intend to focus their research on human studies and work 

directly with people. NIAMS also supports clinical K08 and K23 physician-scientists by offering 

special webinars and meetings to allow them to engage with NIAMS leadership and extramural 

staff. The long-term goal of these meetings is to enhance, encourage, and enable “K-awardees” 

to navigate critical transitions and retain them in independent research careers. 

Clinician-scientists are also encouraged to apply to the NIH Loan Repayment Program (LRP). 

The escalating costs of advanced education and training in medicine and clinical specialties have 

led some scientists to abandon research careers for potentially more lucrative industry or private 

practice careers. The LRP counteracts that financial pressure by repaying a portion of the 

researcher's qualified educational debt in return for a commitment to engage in specified NIH 

mission-relevant research. 

Several NIH and NIAMS programs address the development and retention of mid-career 

scientists. For example, the NIH Mid-career Investigator Award in Patient-Oriented Research 

(K24) provides protected time for mid-career clinicians to conduct research while serving as 

mentors for junior clinical investigators, particularly K23 grantees. The K24 award is intended to 

stabilize the careers of these investigators as they continue their research, directly interacting 

with patients while simultaneously supporting the development of the next generation of clinical 

researchers. 

NIAMS also offers the Supplements to Advance Research (STAR) program to provide additional 

support for investigators to pursue innovative and high-risk research within the broader scope of 

a current NIAMS-funded, peer-reviewed research project. STAR provides supplemental funding 

to investigators who have renewed their first NIAMS R01 grant and aids investigators as they 

work to expand a single, structured research project into a broader multi-faceted research 

program. The STAR program allows space for flexibility, innovation, and risk-taking related to 

the research area of the parent R01 and is optimized to support principal investigators as they 

develop challenging, creative, and innovative scientific endeavors that will sustain a career. 

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Workforce diversity 

A growing body of evidence shows that workforce diversity is associated with creativity and 

innovation—characteristics that are essential for tackling complicated research questions. As the 

Advisory Committee to the NIH Director Working Group on Diversity in the Biomedical 

Research noted in its 2012 report, a workforce that better resembles the population that it serves 

can provide stronger ties with global research networks and improve engagement of 

underrepresented racial and ethnic minorities in community-based studies. Many rare diseases 

and conditions within the NIAMS mission cannot be investigated adequately without 

international research teams and patient cohorts, making this a high priority for the Institute. In 

addition, many forms of arthritis and musculoskeletal and skin diseases disproportionately affect 

Americans from minority racial or ethnic backgrounds. Fostering a research community that 

includes diverse leaders is expected to improve health equity across NIAMS disease areas. 

More than half of the U.S. population under 18 years of age will soon be non-white and many of 

these young people will aspire to enter scientific or biomedical careers in the future. NIAMS is 

committed to making biomedical research careers more attractive to students from traditionally 

underrepresented backgrounds. In addition, NIAMS encourages the inclusion of scientists from 

underrepresented groups in leadership teams and advisory groups to leverage diverse 

perspectives and improve the likelihood of generalizability of research results. 

NIAMS participates in NIH programs designed to attract and encourage individuals from 

underrepresented populations to pursue research careers by providing a continuum of research 

training opportunities, from high school to higher education faculty levels. NIAMS recognizes a 

unique and compelling need to promote diversity in the biomedical, behavioral, and clinical 

research workforce through the Diversity Supplement Program. The overall goal of the program 

is to improve the diversity of the research workforce by recruiting and supporting students, 

postdoctoral researchers, and eligible investigators from diverse backgrounds, including those 

from groups that have been shown to be underrepresented in health-related fields. 

Next Generation Researchers Initiative 

NIAMS has a long-standing history of participation in trans-NIH initiatives and policies 

designed to facilitate early-stage investigators (ESIs) as they transition to independent careers by 

obtaining their first major NIH award. In alignment with the NIH-wide Next Generation 

Researchers Initiative (NGRI), ESI status is considered during review and ESIs are given special 

funding consideration. In addition, the Institute has established processes to give individual 

attention to meritorious applications from investigators who lost, or are at risk of losing, all NIH 

research support, or investigators supported by only one active award. NIAMS will revisit these 

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policies annually to ensure they are reaching programmatic goals and to maintain alignment with 

evolving trans-NIH NGRI policies. 

Innovation 

NIAMS leadership understands that innovation is the basis of scientific progress. It is nearly 

impossible to predict from where the next research direction or great scientific breakthrough will 

emerge; hence the Institute’s strong commitment to investigator-initiated research and the 

process of peer review to identify meritorious proposals. Nevertheless, challenging the status quo 

is often inherently risky, and when resources are constrained review tends to be conservative, 

supporting safe bets rather than high risks. NIH data have shown that of the five standard peer 

review criterion scores, “innovation” is not a primary predictor of funding for R01 applications. 

NIAMS and NIH have implemented programs to promote innovative research concepts and the 

pursuit of scientific hypotheses that could steer science in new directions. For example, the NIH 

Common Fund’s High-Risk, High-Reward Research program supports exceptionally creative 

investigators pursuing highly innovative research with the potential for broad impact in 

biomedical or behavioral science. The program’s four constituent NIH Director’s awards provide 

a diverse set of funding opportunities for outstanding investigators at all career stages. NIAMS 

encourages the pursuit of its mission areas though these opportunities. 

Discoveries in biomedical and behavioral research are often not ready for immediate clinical 

application or commercial development. The NIH Small Business Innovation Research (SBIR) 

and Small Business Technology Transfer (STTR) programs are one mechanism available to 

address this gap. The SBIR/STTR program is one of the largest sources of research funding for 

small businesses and startups and it supports and encourages the translation of research 

discoveries and novel technologies into innovative commercial products. Awards provide 6 

months (SBIR) or 1 year (STTR) of support for proof-of-concept testing and 2 years for research 

and development. The program encourages small businesses to develop new technologies and 

products with potential for commercialization across health domains. The NIAMS 

SBIR/STTR program aims to facilitate the translation of basic discoveries into commercial 

applications within the Institute’s mission areas. 

In addition, NIAMS has initiated the Research Innovations for Scientific Knowledge (RISK) 

program. This novel mechanism focuses on innovative research within the NIAMS mission by 

encouraging applicants to pursue unusual observations, test imaginative hypotheses, investigate 

creative concepts, and build groundbreaking paradigms that deviate significantly from current 

prevailing theories or practice. RISK is particularly designed to encourage the submission of 

projects that are considered too risky, premature, controversial, or unconventional for other NIH 

mechanisms. While the program’s focus is on scientific innovation, the review and funding of 

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proposals is also innovative, including a novel “anonymous” pre-application review phase prior 

to submission of an application for funding consideration. In addition, funded awards provide 

support for up to 2 years to perform critical experiments that rigorously test the proposed 

concept. The outcomes of these experiments are a central factor in determining whether the 

project will continue on to the second phase with additional support to further validate and 

explore the innovative concept. Through the RISK initiative, NIAMS supports bold and eclectic 

ideas and specifically fosters innovative proposals in concert with other NIH research project 

mechanisms. 

The 21st Century Cures Act provides NIH with critical tools and resources to advance 

biomedical research across the spectrum, from foundational basic research studies to advanced 

clinical trials of promising new therapies. As part of the law, multiyear funding for four highly 

innovative scientific initiatives was authorized, including the All of Us Research Program, the 

Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the 

Cancer MoonshotSM, and the Regenerative Medicine Innovation (RMI) Project. NIAMS 

participates in these funding opportunities where there is overlap with the NIAMS mission. For 

example, NIAMS partnered with the National Cancer Institute and the National Institute of 

Allergy and Infectious Diseases on Cancer Moonshot efforts to clarify the relationship between 

cancer, autoimmunity, and immunology, and provided supplements to existing grants for 

research collaborations on immune-related adverse events associated with cancer 

immunotherapy. NIAMS also actively participated in RMI program funding opportunities with 

the goal of accelerating regenerative medicine discoveries related to NIAMS mission and 

enhancing support for innovative clinical research using adult stem cells while promoting the 

highest standards for carrying out scientific research and protecting patient safety. NIAMS plans 

to continue participation in these unique programs. 

Research Partnerships 

NIAMS works closely with other NIH Institutes, Centers, and Offices to leverage their unique 

strengths and avoid duplication of efforts. The Institute continues to encourage investigators to 

leverage research resources generated through the NIH Common Fund or other trans-NIH 

programs. The Institute also works to ensure that NIAMS-supported researchers are represented 

in trans-NIH meetings that are important to our communities. In turn, NIAMS includes 

researchers supported by other NIH Institutes, Centers, and Offices in NIAMS-led meetings, as 

appropriate. 

The breadth of the NIAMS mission and its importance to the Nation’s health is evidenced in the 

involvement of Institute staff in the development of trans-NIH and interagency priority-setting 

documents, such as the following: 

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• Action Plan for Lupus Research (2015)

• 2015 Action Plan for the Muscular Dystrophies

• National Institutes of Health Research Plan on Rehabilitation (2016)

• Federal Pain Research Strategy (2018)

• 2019-2023 Trans-NIH Strategic Plan for Women’s Health Research

• Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention (2019)

• Healthy People 2020 and 2030

Investigators are encouraged to explore these and other resources, as well as the NIH and 

NIAMS Strategic Plans as they look for exciting ideas and opportunities to pursue. The most upto-date list of NIH-wide strategic plans can be found at 

https://report.nih.gov/strategicplans/index.aspx. 

Recognizing the need for collaborations to advance behavioral and biopsychosocial research, 

NIAMS participates in several relevant trans-NIH efforts (e.g., the NIH Pain Consortium and the 

National Center on Sleep Disorders Research) and works closely with the NIH Office of 

Behavioral and Social Sciences Research. These interactions allow the Institute to share 

information about NIAMS-funded research efforts and advances and to form partnerships with 

other NIH components in areas of common interest. 

Below are a few historical examples of partnerships that NIAMS has led or contributed to. The 

resulting data sources are available for arthritis and musculoskeletal and skin researchers to 

leverage as they develop scientific proposals over the next 5 years. 

• In the early 2000s, NIAMS and the National Institute on Aging organized the

Osteoarthritis Initiative (OAI), a public-private partnership that included several NIH

Institutes, Centers, and Offices, the U.S. Food and Drug Administration (FDA), and four

pharmaceutical companies. Today, OAI is a publicly available research resource

containing clinical data, images and specimens from more than 4,500 participants, many

of whom have been involved in the study for more than a decade. Researchers are

welcome to use OAI resources to pose hypotheses about possible OA biomarkers of

disease onset and progression, test their theories, describe the natural history of OA, and

investigate factors that influence disease development and severity. They also can use

OAI to identify potential disease targets and develop tools for measuring clinically

meaningful improvements.

• In 2014, NIAMS joined with the National Institute for Allergy and Infectious Diseases

(NIAID) to lead the Accelerating Medicines Partnership (AMP) program in rheumatoid

arthritis and systemic lupus erythematosus (RA/SLE). AMP is an initiative sponsored by

NIH, biopharmaceutical companies, and several nonprofit organizations to transform the

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current model for developing new diagnostics and treatments. The data generated from 

cutting-edge technologies are being made publicly available for other researchers to 

interrogate through the NIAID-sponsored Immunology Database and Analysis Portal 

(ImmPort), while genomic data are available through NIH’s database of Genotypes and 

Phenotypes (dbGaP). In the coming years, results from the projects are expected to 

improve understanding of the molecular and cellular basis of RA and SLE and of 

heterogeneity among patients with these diseases, providing new opportunities for 

effective, personalized treatments. The data from the project will continue to be an 

important resource for biomedical and clinical research and a potential basis for future 

research collaborations. 

• Until Common Fund support ended in 2014, NIAMS managed the NIH Patient Reported

Outcomes Measurement Information System (PROMIS®), a collaborative initiative

among many NIH Institutes, Centers, and Offices. The purpose of the initiative was to

develop psychometrically robust ways of measuring issues that affect the day-to-day lives

of patients, such as pain, fatigue, physical functioning, emotional distress, and social role

participation across a variety of chronic diseases. These measurement tools can be used to

bring patients’ voices and experiences into clinical research so that interventions being

developed by the research community will, in addition to improving clinical parameters,

address quality of life. Component questions of the PROMIS instrument have been

rigorously tested in culturally and ethnically diverse populations. They can be used to

measure changes in patient-reported outcomes over time and in response to treatments. A

variety of adult and pediatric (including parent proxy) PROMIS® instruments are

available for use in clinical trials, point-of-care visits, or large scale surveys. For more

information about PROMIS®, see Patient-Centric Approaches to Health and Disease in

the section on Cross-cutting Scientific Themes.

• Over the next five years, the Molecular Transducers of Physical Activity Consortium

(MoTrPAC) will be releasing data investigators can use to identify the molecules that

protect against bone, joint, and muscle deterioration and that preserve physical function.

MoTrPAC’s goal is to assemble a comprehensive map of the molecular changes that

occur in response to physical activity and, when possible, relate these changes to the

benefits of physical activity. This map will contain the many molecular signals that

transmit the health effects of physical activity and will indicate how they are altered by

variables such as age, sex, body composition, fitness level, and chronic exposure to

exercise. Information about MoTrPAC resources, animal and clinical protocols, and the

potential for ancillary studies are available at www.motrpac.org.

• Looking to the future, the All of Us Research Program’s one million person cohort will

provide many opportunities regarding a range of NIAMS-related health issues. Immune

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and inflammatory diseases, musculoskeletal and movement disorders, and chronic pain 

conditions are among the topics that comprise the program’s scientific framework. 

Scientific opportunities afforded by All of Us include studies of gene and environment 

interactions, pharmacogenomics, biomarkers, and mobile health technologies. Data will 

be available through the All of Us Research Hub. 

Inclusion of Diverse Populations as Participants in Biomedical 

Research 

As stated previously, many diseases that fall within the NIAMS mission exhibit sex, racial, 

ethnic, and other disparities. Given what is known about the populations affected by these 

diseases, it is critical to ensure that the research the Institute supports appropriately includes a 

diverse group of participants. NIH and NIAMS are committed to the inclusion of women and 

minorities in all NIH-funded clinical research. This is demonstrated through implementation of 

the NIH Revitalization Act of 1993 (Public Law 103-43), which requires inclusion of women 

and members of minority groups and their subpopulations in NIH-funded clinical research, 

including clinical trials, unless there is appropriate justification for not including them. 

Researchers need to consider factors such as sex, race, ethnicity, and socioeconomic status in the 

design, data collection, and analysis of clinical research studies and clinical trials. These studies 

serve as resources for data that could be leveraged to answer important, fundamental questions in 

health disparities research. 

The 21st Century Cures Act (Public Law 114 -255), enacted in 2016, introduced new 

requirements related to inclusion of participants in clinical research. As a result, NIH updated its 

policy on the Inclusion of Women and Minorities as Subjects in Clinical Research. Additionally, 

NIH revised its Inclusion of Children Policy, which is now called the NIH Policy and Guidelines 

on the Inclusion of Individuals Across the Lifespan, to ensure that clinical research includes 

individuals of all ages unless there is an appropriate justification to do otherwise. 

In addition to the efforts described above that relate to clinical research, NIH also encourages 

enhanced attention to sex as a critical factor in basic and preclinical studies. In 2015, the agency 

announced a policy on Consideration of Sex as a Biological Variable to foster research that 

improves understanding of the biology underlying sex differences and provides knowledge to 

improve the health of women, men, girls, and boys. NIAMS supports NIH’s overarching efforts 

on studying sex and gender, which call on researchers to take sex into account as they develop 

their research questions, design experiments, analyze data, and report results. 

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Performance Measures and Assessment 

NIAMS, like NIH as a whole, supports research with the ultimate goal of curing disease and 

improving overall health. However, significant time elapses between basic discovery and 

development of clinical applications. Scientific discovery often involves years to decades worth 

of incremental advances that are critical to achieving the ultimate goal of turning discovery into 

health. While a direct link can sometimes be drawn between specific funding and an 

improvement in health, most often the story is complex. Thus, determining the extent to which 

NIAMS has met the objective of improving health can be a challenge. Furthermore, over the 

course of a 5-year period the scientific field can advance and evolve in many unanticipated ways. 

As noted in the Director’s Message, these unexpected breakthroughs also serve as indicators of 

progress and are a successful outcome of support. With this in mind, NIAMS will adopt a mixed 

methods approach that balances quantitative and qualitative methods to examine outputs and 

outcomes from this Strategic Plan for FYs 2020-2024. 

An important management component at NIAMS is a planning and priority-setting process that 

incorporates input from the scientific community. The Institute’s focus on investigator-initiated 

research applications and identification of the most promising research projects through peer 

review requires performance measures that reflect the full scope of the NIAMS mission and the 

work funded based on these processes. In addition to the investigator-initiated peer-review 

process, NIAMS uses evidence-based information when making decisions about scientific 

programs and conducts quantitative or qualitative assessments of programs and research topics to 

guide activities. With a growing evolution in the use of evidence to inform policy decisions, the 

performance measures and metrics NIAMS uses may be adjusted and should be evaluated 

regularly to ensure they are providing the information needed to guide priority setting efforts. 

This section reiterates some of the ways in which NIAMS currently uses data to inform decision 

making and discusses several potential measures that NIAMS may use in the future to assess its 

research portfolio and progress toward its scientific objectives of advancing and accelerating 

research within its mission. 

Investigator-initiated research supported by NIAMS, through funding mechanisms such as R01 

awards, is conducted across the Institute’s disease- and tissue-specific mission areas described in 

this plan. Working with partners across NIH, such as the Office of Portfolio Analysis, Office of 

Evaluation, Performance, and Reporting, and other NIH components, NIAMS will identify 

appropriate measures and tools for a particular portfolio analysis and evaluation. For 

investigator-initiated research, such assessments could be used to evaluate and monitor 

innovation that results from this funding pool or to help guide select pay decisions and gauge 

their effects. 

132 
 

 

NIAMS also supports targeted programs that focus on early-stage investigators, high-risk 

research with potential to drive innovation, or establishing research resources for use by the 

larger scientific community, such as the OAI and AMP. For targeted efforts, NIAMS uses 

evaluation tools and data-driven assessments to help inform the creation of new programs and to 

revise and re-issue funding opportunity announcements for existing programs. Several examples 

of assessments of targeted programs are highlighted throughout this Strategic Plan. The section 

on Priority Setting notes that program assessments have shaped changes to the NIAMS 

Supplements to Advance Research (STAR) program and the Small Grant Program (R03). The 

section on Advancing and Accelerating Muscle Biology and Disease Research describes an 

evaluation of the Wellstone Centers program and how that effort is being used to identify 

program changes that could enhance efforts to achieve the Centers’ goals. Assessment of 

targeted programs over the short- and long-term will rely on both quantitative and qualitative 

measures and may include analysis of career trajectories for trainees and early-stage investigators 

or significant advances spurred by targeted program efforts. Moving forward, NIAMS will 

continue to use approaches that may include, but are not limited to, an analysis of outputs (e.g., 

publications, development of new methods), outcomes (e.g., significant conceptual advances, 

stories of discovery, influential papers), and bench-to-bedside translation resulting from 

supported research. 

Consistent with the Institute’s emphasis on collecting stakeholder input, NIAMS will continue to 

hold roundtable discussions to assess research gaps and opportunities in specific mission areas, 

cross-cutting scientific themes, and clinical research efforts. NIAMS may also engage the 

community through listening sessions with researchers and NIAMS Coalition members to 

identify emerging research directions that could benefit from Institute encouragement. 

Finally, NIAMS will work to ensure that the performance measure development and 

implementation process is incorporated across the Institute. Defining success prior to the launch 

of a new concept will facilitate gathering data to measure progress and allow identification of 

adjustments to improve performance. 

Information Dissemination and Outreach 

The driving force behind NIAMS-funded research is to improve the lives of those who are 

affected by diseases and conditions of bones, joints, muscles, and skin. Sharing information 

about research progress and conducting outreach to multiple audiences are essential components 

of the NIAMS mission. The Institute is committed to communicating research advances to all 

segments of the public. 

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Information dissemination 

The Institute is dedicated to working closely with grantees and their institutions to disseminate 

research findings to constituents via multiple venues. Key priorities include: 

• Enhance access to reliable, audience-appropriate health information in multiple languages

and formats, with an emphasis on electronic offerings (see Information Dissemination

and Outreach Resources FAQs section below); and

• Raise awareness of NIAMS-supported research through plain language materials that are

widely disseminated through multiple channels, including social media.

NIAMS will continue to support and operate the NIAMS Information Clearinghouse and the 

NIH Osteoporosis and Related Bone Diseases ~ National Resource Center (NRC). Both 

clearinghouses distribute health information materials to patients, allied health professionals, 

voluntary and professional organizations, underserved and at-risk populations, the media, and the 

general public. The NIAMS Information Clearinghouse provides materials on diseases and 

conditions of bones, joints, muscles, and skin in a variety of formats and languages. 

The NRC provides an important link to resources and information on metabolic bone diseases 

including osteoporosis, Paget’s disease of bone, and osteogenesis imperfecta. It is supported by 

NIAMS, with contributions from the National Institute on Aging, the National Institute of

Diabetes and Digestive and Kidney Diseases, and the NIH Office of Research on Women’s

Health.

Social media has increasingly become a primary avenue through which people receive news and 

information, as well as a main vehicle for communicating with individuals and organizations 

alike. NIAMS has fully integrated social media into its information dissemination program. The 

Institute posts regular updates to Twitter (@NIH_NIAMS) and Facebook (NIH.NIAMS), 

featuring NIAMS health information, recently published research articles, news and 

announcements, training and funding opportunities, and other information and resources. 

NIAMS hosts live social media events with other NIH Institutes, Centers, and Offices and 

professional and voluntary organizations to address timely health topics. NIAMS regularly posts 

videos on its YouTube channel and scientific images on its Flickr photo stream. NIAMS will 

continue to evaluate efforts to reach more constituents through social media channels and to 

explore integration of other social media tools to target and increase direct interaction with 

diverse audiences. 

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Information Dissemination and Outreach Resources FAQs 

What sort of plain-language materials does NIAMS offer? 

NIAMS develops health information materials for patients and their families, health care 

providers, and the general public. NIAMS offers many of its materials in easy-to-read 

English formats, as well as in several other languages including Spanish, Chinese, Korean, 

and Vietnamese. A separate Spanish web portal and Asian languages web section let visitors 

easily access information in different languages. 

How can a constituent stay informed about NIAMS activities? 

The Institute produces several e-newsletters that are available by easy online subscription. 

These include the NIAMS Update, an electronic digest for those interested in the latest 

NIAMS/NIH-supported scientific news and resources on diseases of bones, joints, muscles, 

and skin. The Institute also develops the NIAMS Community Outreach Bulletin, an online 

digest designed to inform community organizers and health professionals about resources for 

diverse audiences. In addition, NIAMS disseminates Honoring Health: Resources for 

American Indians and Alaska Natives. Institute updates are also available through several 

social media channels. 

Where can someone find answers to questions about NIAMS, its research, or its health 

information? 

The NIAMS clearinghouses have bilingual Spanish/English information specialists who 

respond to public inquiries about topics under the NIAMS purview. Assistance is easily 

available via phone, email, or letter (see Contact Us). 

Looking ahead, NIAMS will continue to respond to the increased demand for online health and 

research information. The NIAMS website has been redesigned to be easily viewed on a phone, 

tablet, or computer. This key outreach platform will be regularly updated and refined based on 

user metrics and content development, in alignment with the NIAMS mission. 

Outreach 

The Institute is dedicated to engaging the public and encouraging broad participation and input in 

NIAMS and NIH activities. Upcoming plans in this area include: 

• Increase the visibility of NIAMS as a leading resource for information on diseases and

conditions of bones, joints, muscles, and skin; and

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• Expand awareness among scientists and students at all education levels about career and 

training opportunities in biomedical research fields in NIAMS mission areas, particularly 

in underrepresented communities. 

The Institute works closely with the NIAMS Coalition to share research advances and related 

developments, as well as to foster dialogue on future paths and directions of NIAMS-funded 

research. The Coalition is an independent consortium of professional and voluntary organizations 

that works to raise awareness about NIAMS research into the basic understanding, causes, 

treatment, and prevention of diseases of bones, joints, muscles, and skin. The Coalition plays a 

vital role as a voice of the researchers and patients for whom NIAMS works. The Institute will 

continue to engage regularly with Coalition partners through teleconferences and webinars, inperson meetings, and presentations at professional and voluntary meetings. 

NIAMS will continue its Community Outreach Initiative to ensure that resources reach diverse 

populations. Through development and distribution of an e-newsletter, a social media toolkit, 

and other materials, health care providers and community organizers in multicultural 

communities nationwide receive access to health information and resources about health 

conditions that affect bones, joints, muscles and skin. In addition, NIAMS has implemented a 

Language Access Plan as part of NIH-wide efforts to help ensure that people who have limited 

English proficiency have meaningful access to all NIAMS programs and activities. 

To broaden outreach to underrepresented groups, NIAMS is taking an active role in leading the 

NIH American Indian/Alaska Native (AI/AN) Health Communications and Information Work 

Group, a collaboration that represents more than 20 NIH Institutes, Centers, and Offices. The 

working group partners with the Indian Health Service (IHS) and the Administration on 

Aging/Administration for Community Living to develop and disseminate health information to 

IHS community health representatives and Title VI grantees nationwide. 

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APPENDICES 

Appendix 1: Overview of the Development Process 

The NIAMS Strategic Plan for Fiscal Years (FYs) 2020-2024 continues to build on the 

foundation of the Institute’s previous long-range plans. It also includes new additions to feature 

four broad cross-cutting scientific themes, selected based on input from the community, that are 

relevant to all, or most, of the disease- and tissue-specific topics within the NIAMS mission and 

to address NIH and NIAMS initiatives related to management, scientific stewardship, and 

accountability. 

NIAMS solicited comments on how the NIAMS Long-Range Plan for FYs 2015-2019 should be 

updated via a Request for Information (RFI) (Appendix 2) and gathered additional information 

through listening sessions with the NIAMS stakeholder communities. 

The RFI was posted on the NIAMS website and in the NIH Guide for Grants and Contracts, and 

it encouraged feedback from researchers in academia and industry, health care professionals, 

patient advocates and health advocacy organizations, scientific and professional organizations, 

Federal agencies, and other interested members of the public. Information about the RFI was 

shared in emails to grantees, NIAMS Coalition members, and NIH components to encourage 

broad response. The comment period spanned 6 weeks. Respondents were asked to provide input 

on research needs and opportunities that should be modified because of progress over the last 5 

years, emerging research needs and opportunities that should be added, and cross-cutting 

scientific themes or research-related themes common to all, or most, of the disease- and tissuespecific topics within the NIAMS mission that should be included. General comments were also 

encouraged. 

In November and December 2018, seven listening sessions were held with more than 100 

individuals. The listening session participants consisted of researchers and patients representing 

systemic rheumatic and autoimmune diseases, skin biology and diseases, muscle biology and 

diseases, bone biology and diseases, joint biology, diseases, and orthopaedics, as well as 

members of the NIAMS Coalition, a group of more than 90 professional and voluntary 

organizations interested in the Institute’s mission areas. Six of the listening sessions were held 

via conference calls. The seventh session was an in-person meeting with established researchers 

and professional and voluntary organization representatives who attended the NIAMS K Forum 

for Clinical Mentored K Awardees. All listening session participants were encouraged to gather 

and share the views of the broader research community by consulting a diverse set of colleagues 

in advance of the listening sessions. In addition to providing input on their tissue- or disease137 
 

 

 

 

specific topic, participants were asked about needs and opportunities that could be included in 

the new section of the plan on cross-cutting scientific themes. Part of the discussion was also 

devoted to health disparities and training and career development. Further, participants in the 

listening session with the NIAMS Coalition provided input on how the new NIAMS Strategic 

Plan for FYs 2020-2024 could be structured to be most useful to NIAMS varied stakeholders. 

Updates on the development of the NIAMS Strategic Plan for FYs 2020-2024 were provided at 

the September 2018 and February 2019 Advisory Council meetings. In February 2019, the 

NIAMS Acting Director convened a Working Group of the Advisory Council to review the draft 

plan, which was presented to the Working Group and Advisory Council in May 2019. The 

NIAMS Advisory Council Working Group for the Strategic Plan discussed the draft plan via a 

conference call in May 2019 and reported their findings and recommendations at the June 2019 

Advisory Council meeting. Feedback from the Working Group and Advisory Council was 

incorporated into the draft plan after the meeting. 

The Institute then issued a second RFI to invite public comments on the revised draft plan. The 

RFI was published in the NIH Guide for Grants and Contracts and information posted on the 

NIAMS website (Appendix 2). The comment period spanned 3 weeks. In addition to the 

outreach efforts similar to those associated with the first RFI, the Institute also issued a Federal 

Register Notice to further publicize this RFI. All comments received were reviewed carefully by 

Institute staff and incorporated into the document, as appropriate. 

The final version of the NIAMS Strategic Plan for FYs 2020-2024 was presented to the NIAMS 

Advisory Council at the Council’s September 2019 meeting. After clearance to ensure 

compliance with the requirements described in the 21st Century Cure Act, the NIAMS Strategic 

Plan for FYs 2020-2024 was posted on the Institute’s public website and widely disseminated to 

NIAMS communities. 

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Appendix 2: Requests for Information Published in the NIH Guide 

for Grants and Contracts 

During the development of the National Institute of Arthritis and Musculoskeletal and Skin 

Diseases (NIAMS) Strategic Plan for Fiscal Years (FYs) 2020-2024, the Institute issued two 

Requests for Information: the first to solicit initial comments on how the previous plan for 

FYs 2015-2019 should be modified to reflect progress over the past 5 years, and the second to 

invite public feedback on the draft NIAMS Strategic Plan for FYs 2020-2024. 

Request for Information (RFI) on the National Institute of Arthritis and Musculoskeletal 

and Skin Diseases (NIAMS) Strategic Plan for Fiscal Years (FYs) 2020-2024 

Notice Number: NOT-AR-19-009 

Key Dates 

Release Date: September 14, 2018 

Response Date: October 26, 2018 

Issued by 

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 

Purpose 

Background 

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is 

updating its Long-Range Plan to help guide the research it supports over the next 5 years. 

Public input on the topics to be included in the plan and suggestions regarding how to enhance 

the NIAMS research portfolio are critical initial steps in this effort. NIAMS leadership and 

staff will review and consider the comments as the Institute updates its Long-Range Plan. 

Information Requested 

Through this RFI, NIAMS invites feedback from researchers in academia and industry, health 

care professionals, patient advocates and health advocacy organizations, scientific or 

professional organizations, Federal agencies, and other interested members of the public. 

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Organizations are strongly encouraged to submit a single response that reflects the views of 

their organization and membership as a whole. 

Please provide your perspective on the following issues: 

• Research opportunities in the NIAMS Long-Range Plan for Fiscal Years (FY) 2015-

2019 that should be modified because of progress over the past 5 years. 

• Emerging research needs and opportunities that should be added to the plan. 

• Cross-cutting scientific themes (e.g., pain, regenerative medicine) or research-related 

themes (e.g., innovation) common to all, or most, of the disease and tissue-specific 

topics (systemic rheumatic and autoimmune diseases, skin biology and diseases, bone 

biology and diseases, joint biology and diseases and orthopaedics, and muscle biology 

and diseases) within the NIAMS mission that should be included in the plan. 

NIAMS also welcomes your general comments, including those regarding the extent to which 

the FYs 2015-2019 Plan has guided and encouraged the field. 

When commenting on a research need or opportunity, your comments can contain but are not 

limited to information pertaining to the following: 

• Description of the opportunity: Addressing an existing component of the FYs 2015-

2019 Plan that should be modified due to progress over the past 5 years, or a new 

opportunity for research not covered in the FYs 2015-2019 Plan. 

• Rationale: The scientific evidence or clinical basis for the proposed change or addition 

and the anticipated impacts that accomplishments or advances related to this issue 

would have on the scientific community and human health. 

How to Submit a Response 

Responses to this RFI must be submitted electronically 

at https://grants.nih.gov/grants/rfi/rfi.cfm?ID=81. 

Responses must be received by October 26, 2018. 

Responses to this RFI are voluntary. Do not include any proprietary, classified, 

confidential, trade secret, or sensitive information in your response. The responses will be 

reviewed by NIAMS staff, and individual feedback will not be provided to any responder. 

NIAMS will use the information submitted in response to this RFI at its discretion and will 

not provide comments to any responder’s submission. Respondents are advised that the 

Government is under no obligation to acknowledge receipt of the information received or 

140 
 

 

 

 

 

 

 

 

 

 

 

 

provide feedback to respondents with respect to any information submitted. The Government 

reserves the right to use any submitted information on public NIH websites, in reports, in 

summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or 

cooperative agreement(s), or in the development of future funding opportunity 

announcements. 

This RFI is for information and planning purposes only and shall not be construed as a 

solicitation, grant, or cooperative agreement, or as an obligation on the part of the Federal 

Government, the NIH, or individual NIH Institutes and Centers to provide support for any 

ideas identified in response to it. The Government will not pay for the preparation of any 

information submitted or for the Government’s use of such information. No basis for claims 

against the U.S. Government shall arise as a result of a response to this request for 

information or from the Government’s use of such information. 

We look forward to your input and hope that you will share this RFI document with your 

colleagues. 

Inquiries 

Please direct all inquiries to: 

Cindy Caughman, M.P.H. 

Chief, Science Policy and Planning Branch 

National Institute of Arthritis and Musculoskeletal and Skin Diseases 

Telephone: 301-496-8190 

Email: niamslrpfeedback@mail.nih.gov 

Request for Information (RFI) on the National Institute of Arthritis and Musculoskeletal 

and Skin Diseases (NIAMS) Strategic Plan for Fiscal Years (FYs) 2020-2024 

Notice Number: NOT-AR-19-010 

Key Dates 

Release Date: June 21, 2019 

Response Date: July 12, 2019 

Related Announcements 

NOT-AR-19-009 

Issued by 

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 

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Purpose 

Background 

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is 

updating its Strategic Plan for Fiscal Years 2020-2024 to help guide the research it supports 

over the next 5 years. The Institute issued a previous Request for Information (NOT-AR-19-

009) to solicit initial comments on how the previous plan for fiscal years 2015-2019 should be 

modified to reflect progress over the past 5 years. The Institute also gathered additional input 

through listening sessions with the community. Based on this feedback, along with input from 

the NIAMS Advisory Council and its Working Group for the Strategic Plan, the Institute has 

drafted the NIAMS Strategic Plan for FYs 2020–2024 

(https://grants.nih.gov/grants/rfi/NIAMS-Strategic-Plan-2020-2024.pdf). We are now seeking 

input on this draft. 

Information Requested 

Through this RFI, NIAMS invites feedback from researchers in academia and industry, health 

care professionals, patient advocates and health advocacy organizations, scientific or 

professional organizations, Federal agencies, and other interested members of the public on 

the draft NIAMS Strategic Plan for FYs 2020-2024 (https://grants.nih.gov/grants/rfi/NIAMSStrategic-Plan-2020-2024.pdf). 

Organizations are strongly encouraged to submit a single response that reflects the views of 

their organization and membership as a whole. 

Please provide your comments and feedback. The final draft of the Strategic Plan will be 

presented at the September 2019 meeting of the NIAMS Advisory Council and posted on the 

NIAMS website when it is approved. 

How to Respond 

Responses to this RFI must be submitted electronically 

at http://grants.nih.gov/grants/rfi/rfi.cfm?ID=89. 

Responses must be received by July 12, 2019. 

Responses to this RFI are voluntary. Do not include any proprietary, classified, 

confidential, trade secret, or sensitive information in your response. The responses will be 

142 
 

 

 

 

 

 

 

 

 

 

 

 

 

reviewed by NIAMS staff, and individual feedback will not be provided to any responder. 

NIAMS will use the information submitted in response to this RFI at its discretion and will 

not provide comments to any responder’s submission. Respondents are advised that the 

Government is under no obligation to acknowledge receipt of the information received or 

provide feedback to respondents with respect to any information submitted. The Government 

reserves the right to use any submitted information on public NIH websites, in reports, in 

summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or 

cooperative agreement(s), or in the development of future funding opportunity 

announcements. 

This RFI is for information and planning purposes only and shall not be construed as a 

solicitation, grant, or cooperative agreement, or as an obligation on the part of the Federal 

Government, the NIH, or individual NIH Institutes and Centers to provide support for any 

ideas identified in response to it. The Government will not pay for the preparation of any 

information submitted or for the Government’s use of such information. No basis for claims 

against the U.S. Government shall arise as a result of a response to this request for 

information or from the Government’s use of such information. 

We look forward to your input and hope that you will share this RFI document with your 

colleagues. 

Inquiries 

Please direct all inquiries to: 

Cindy Caughman, M.P.H. 

Chief, Scientific Planning, Policy, and Analysis Branch 

National Institute of Arthritis and Musculoskeletal and Skin Diseases 

Telephone: 301-496-8271 

Email: niamslrpfeedback@mail.nih.gov 

143 
Appendix 3: Development Timeline for the NIAMS Strategic Plan 

for Fiscal Years 2020-2024 

2018 September Update to NIAMS Advisory Council on the development of the plan. 

September/ 

October 

Request for Information posted in the NIH Guide for Grants and 

Contracts and on the NIAMS website for public input on research 

opportunities that should be modified because of progress over the past 

5 years, emerging research needs and opportunities that should be 

added to the plan, and cross-cutting scientific themes or researchrelated themes common to all, or most, of the disease- and tissuespecific topics within the NIAMS mission that should be included in 

the plan. 

November/ 

December 

Listening sessions held as teleconferences for: 

• systemic rheumatic and autoimmune diseases 

• skin biology and diseases 

• muscle biology and diseases 

• bone biology and diseases 

• joint biology, diseases, and orthopaedics 

• NIAMS Coalition 

Listening session for training and health disparities with participants 

who attended the NIAMS Forum for Clinical Mentored K Awardees 

2019 February • Update to NIAMS Advisory Council on the development of the 

plan. 

• NIAMS Advisory Council Working Group for the Strategic 

Plan convened. 

May Draft plan presented to the NIAMS Advisory Council and its Working 

Group for the Strategic Plan for review and input. 

June/July • Report and recommendations from the Working Group 

presented to NIAMS Advisory Council for discussion. 

• Draft plan and a Request for Information posted in the NIH 

Guide and on the NIAMS website to gather public input. 

August Review of public comments on draft plan and updates incorporated, as 

appropriate. 

September Final plan presented to NIAMS Advisory Council and posted on the 

Institute’s website. 

144