NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterisation of the Structure and Mechanical Properties of the Superficial Zone of Articular Cartilage using Multiphoton Microscopy
Funder: Arthritis Research UK

Abstract: The surface zone of articular cartilage is exposed to different patterns of mechanical loading than the underlying tissue, including shear forces generated by movement of the adjacent cartilage or meniscus. It differs in cell content and morphology and in the collagen organisation and proteoglycan content of its extracellular matrix. An extensive elastin fibre network has also recently been reported exclusively in the surface zone. The relationships between these structural specialisations and functional mechanics and the micromechanical basis of surface fibrillation, an early indicator of degeneration, are both poorly understood. We therefore propose to investigate the micromechanical properties of the surface zone of normal and degenerate cartilage. Multiphoton microscopy will enable us, for the first time, to visualise the 3-D organisation of the collagen and elastic fibre networks and cells in fresh, unstained cartilage mounted in micro-mechanical testing apparatuses. Image based meshing will be used to determine strains in each tissue component and thence to develop structurally based finite element models from which the responses of the tissue components to compressive, tensile and shear loading will be quantified. These studies should identify the functionally significant changes in early surface degeneration, as potential targets for therapy and in vivo monitoring.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Peripheral and Central Processing of Osteoarthritic Pain
Funder: Arthritis Research UK

Abstract: Pain mostly originates from peripheral processes and is a conscious experience through higher brain mechanisms. We aim to study key “bottom-up” to ”top-down” events, examining novel mechanisms at several levels. Osteoarthritis, (OA) is often associated with chronic debilitating joint pain, the main complaint in patients [1]. However, in the majority of patients, current pharmacological treatments do not provide full pain relief and are not well tolerated [2]._x000D_ _x000D_ Patients commonly report that their pain goes after joint replacement, suggesting ongoing peripheral drives maintaining the pain. In a preclinical model of OA, using electrophysiological and behavioural measures and selective drugs, we will investigate novel peripheral nerve sodium channel function, based on a large recent body of translational and clinical evidence. Other studies and the presence of significant co-morbidities in patients also suggest dysfunction of central mechanisms [3-5]. We will, therefore, study how spinal processing of joint inputs and defined brainstem events contribute to central sensitisation and abnormal processing of tissue damage pain. In particular we aim to understand how peripheral, spinal and limbic functions can interact within integrated systems. This will enable better understanding of the underlying mechanisms of the pain, which should lead to new therapeutic options.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Prevention of external fixator pin site infection (PSI) with a novel antibiotic-impregnated collar
Funder: Arthritis Research UK

Abstract: Infection involving pins used for fracture management is a serious problem (> 40% infection) with potentially devastating consequences. Our overall objective is to evaluate the use of an antimicrobial collar placed around pin sites in reducing infection._x000D_ _x000D_ Audit and confirmation of causative bacteria: A prospective clinical audit of PSI and isolation of causative bacteria will determine the frequency of PSI, the patient groups most at risk, and the bacteria responsible. The bacteria will then be used in subsequent laboratory tests._x000D_ _x000D_ Development of antimicrobial collar. Using established technology, silicone test discs will be impregnated with combinations of antimicrobials appropriate to the bacteria isolated during the audit. Duration of antimicrobial activity and development of resistance will be the major outcomes. Based on results, a silicone collar will be designed and impregnated with a combination of antimicrobials. These will then be tested in vitro in the track migration model._x000D_ _x000D_ Determination of Clinical Efficacy. Antimicrobial collars will be used in a pilot clinical study and reduction in PSI, development of resistance, irritation/ hypersensitivity, and patient satisfaction will be monitored. Accepted clinical grading systems will be used._x000D_ _x000D_ Cost –effectiveness. This will be calculated from audit and pilot study results in collaboration with Health Economics experts.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: 'Developing effective, deliverable and affordable models of care for the management of chronic knee pain and osteoarthritis within a community setting’.
Funder: Arthritis Research UK

Abstract: Chronic musculoskeletal pain is disabling and poses considerable healthcare costs. Current guidelines recommend exercise and self-management interventions, delivered in primary care by healthcare professionals. These interventions are likely to be unsustainable as the affected population grows and NHS resources are increasingly stretched. Therefore new models of care are required to facilitate effective clinical and cost-efficient care for long-term conditions._x000D_ _x000D_ This Fellowship application proposes the development of a community-based model that encourages exercise, self-management and social interaction as means of encouraging long-term adherence to lifestyle change. It would be delivered by professional and trained non-professional staff at appropriate points of the management pathway. This novel approach supports both Government and Arthritis Research-UK objectives that encourage community-based care and promote social participation._x000D_ _x000D_ The series of studies would consider the suitability of the proposed model to service users, professionals and exercise facilitators. It would ensure training needs are met to an appropriate level, and would pilot the intervention, thus facilitating an appropriately powered clinical trial in the future._x000D_ _x000D_ If successful, this model may be suitable for managing people with widespread osteoarthritis or degenerative pain, ensuring that growing numbers of affected individuals receive clinical and cost-effective management and support in an appropriate setting.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL
Title: Identification of factors regulating TIMP-3 trafficking and activity in cartilage: a novel target for treating osteoarthritis.
Funder: Arthritis Research UK

Abstract: The long-term objective of my research programme is to identify the factors underpinning the increased degradation of the cartilage extracellular matrix that leads to osteoarthritis (OA). Tissue inhibitor of metalloproteinases 3 (TIMP-3) occupies a pivotal role in protecting cartilage by inhibiting the activity of matrix-degrading metalloproteinases and aggrecanases. I have established that the levels and activity of TIMP-3 can be strongly post-translationally regulated, with the protein either being endocytosed and degraded by chondrocytes, or binding to cartilage matrix proteoglycans. I additionally found that sulfated glycosaminoglycans greatly increase TIMP-3 affinity for aggrecanases in vitro, suggesting that sulfated matrix proteoglycans may similarly improve the inhibitory activity of TIMP-3. I hypothesise that TIMP-3 activity is regulated by the balance between endocytosis and matrix binding, and aim to identify whether the observed decrease in TIMP-3 levels in OA cartilage is due to an increase in TIMP-3 endocytosis or a reduction in matrix binding. The molecular mechanisms and importance of matrix binding will be identified, enabling design of a TIMP-3 mutant that can be maintained in cartilage at higher levels. Understanding the factors regulating TIMP-3 trafficking will open novel avenues for the development of disease-modifying OA drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Novel Osteoarthritis gene target discovery and validation of the zebrafish model system for Osteoarthritis research
Funder: Arthritis Research UK

Abstract: To understand pathological conditions such as Osteoarthritis (OA) we need to understand how the correct balance between bone and cartilage is maintained. Many OA susceptibility genes are expressed during early cartilage and joint development. Moreover, blocking endochondral ossification processes can reduce OA progression. Therefore, a better understanding of endochondral ossification in normal and mutant situations is likely to lead to new therapeutic targets for OA._x000D_ _x000D_ My research has identified five zebrafish mutants with developmental phenotype of considerable clinical relevance; decreased cartilage matrix, combined with premature osteoblast differentiation and cartilage mineralisation. The phenotype includes progressive joint abnormalities sharing characteristics with OA._x000D_ _x000D_ Combining the excellent genetics and imaging advantages of zebrafish with traditional matrix biochemistry will allow me to address how the composition of the cartilage matrix affects osteoblast differentiation in vivo._x000D_ _x000D_ This project has three aims: (1) Identification of the genes causing the mutant phenotypes. (2) Phenotypic characterisation of the mutants. (3) Investigation of the effect of cartilage matrix composition on skeletogenic signalling and growth factor diffusion (using transgenic lines)._x000D_ _x000D_ In summary this project aims to identify how cartilage matrix controls the balance between bone and cartilage during development and disease, in the hope/expectation of identifying new therapeutic targets for OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Exploring back pain Patients' perceptions of Important Change (EPIC)
Funder: Arthritis Research UK

Abstract: Low back pain (LBP) is a common complaint incurring considerable cost. Many LBP trials have been conducted but these are difficult to interpret: many therapies seem to offer only small to moderate benefits. In part this may be due to the heterogeneity of participants in trials and our inability to meaningfully subgroup patients, but it may also be because we are not measuring optimal outcomes. Many researchers believe we need to develop a series of new 'next-generation' outcomes and involve patients in their development. The objectives of this research programme are to explore which outcomes are most important from the patient's perspective. We will explore this first in a systematic review and meta-synthesis of qualitative literature and then in a series of in-depth interviews with back pain trial participants. The results will enable us either to reaffirm current outcomes are measuring the correct domains or to highlight areas in which current outcomes are deficient and inform the development of new instruments.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Protection against glucocorticoid and forkhead/sirtuin regulated tendon degeneration
Funder: Arthritis Research UK

Abstract: Over 500,000 glucocorticoid injections are given annually in the UK, most commonly to treat chronic pain in tendons. Degenerative rotator cuff disease alone affects an estimated 20% of UK adults. However glucocorticoids themselves cause tendon degeneration. We found glucocorticoids induced expression of FOXO1 and FOXO3a forkhead transcription factors whilst inhibiting expression of sirtuin 5 in cultured human tenocytes. Altered forkhead and sirtuin expression is known to cause degeneration in other tissues. We also found that insulin or vitamin C inhibited glucocorticoid-induced up-regulation of forkheads and protected against the deleterious effects of glucocorticoids on tenocyte number and collagen output. Using newly-developed techniques to transfect primary human tenocytes, we will determine the roles of FOXO1, FOXO3a and Sirt5 in regulating tenocyte proliferation and activity. We will also determine the causal relationship between forkhead/sirtuin modulation and the established effects of glucocorticoids on tenocyte number and activity and screen clinically-translatable agents for their ability to protect against negative effects of glucocorticoids/forkheads in tendon. We have recently found that forkhead signalling is also upregulated in non-glucocorticoid-treated degenerative tendon suggesting forkhead signalling may contribute to disease pathogenesis. Strategies which protect against glucocorticoid-induced tendon degeneration may therefore also prove efficacious in combating disease-induced tendon degeneration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Chondrocyte ER stress as a pathogenic factor in osteoarthritis
Funder: Arthritis Research UK

Abstract: Chondrocytes synthesise and secrete large quantities of proteins and proteoglycans in order to form and maintain healthy cartilage. Overload of the secretory pathway in cells causes a specific form of cell stress known as endoplasmic reticulum (ER) stress. Chondrocytes in osteoarthritis and various chondrodysplasias exhibit clear signs of ER stress. Such stress can disrupt other normal cellular functions and ER stress is recognised as a significant pathogenic factor in a number of diseases . We will test the hypothesis that the increased ER stress exhibited by articular chondrocytes in OA cartilage plays an active role in the disease process’ by answering the following questions. Do increases in chondrocyte ER stress have the capacity to initiate OA and if so, how? Do increases in chondrocyte ER stress exacerbate the cartilage damage in OA and if so, how? What is the relationship between increased mechanical stress on articular cartilage and chondrocyte ER stress? Defining the precise role of ER stress in the pathogenesis of OA may open up potential new therapeutic avenues based on the pharmacological alleviation of ER stress.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Identification and functional analysis of polymorphisms within the RANK signalling pathway associated with low BMD.
Funder: Arthritis Research UK

Abstract: Post-menopausal osteoporosis is the most common osteoclast-driven disease, associated with low bone mineral density (BMD) and pathological fractures. It presents a major socio-economic burden, and targeting therapies to those most likely to develop low BMD is paramount for this multi-factorial disease. The Receptor Activator of NFκB (RANK) signalling pathway is critical for bone-resorbing osteoclasts, with mutation of genes within this pathway causing severe monogenic disorders of osteoclast dysfunction. Common variants in RANK, RANK Ligand and Osteoprotegerin were recently associated with low BMD in genome-wide association studies, but little is known about functional genetic variation within the whole RANK signalling pathway in relation to BMD. We will directly sequence 25 key genes within this pathway in individuals with extremes of BMD to identify variants potentially associated with low BMD. We will then genotype the Aberdeen Prospective Osteoporosis Screening Study population to assess association of identified variants with low BMD, and perform cell-based studies to examine effects of associated variants on activation of the RANK signalling pathway. This systematic analysis of genetic variation within the RANK signalling pathway will identify potential genetic factors that could be included in cost-effective risk assessment strategies to target therapies for osteoporosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Optimising Vitamin D Status in Older People: A Randomised Controlled Trial of Vitamin D Supplementation
Funder: Arthritis Research UK

Abstract: Vitamin D insufficiency is common in older people, where it may lead to secondary hyperparathyroidism, increased bone resorption, bone loss (reflected by lower bone mineral density (BMD)), impaired muscle function and falls and fractures. Interventional trials of vitamin D supplementation have yielded conflicting results relating to risk of falls and fractures; and it is unclear what the optimal plasma 25 hydroxyvitamin D (25OHD) is for skeletal health. We therefore plan to perform a randomised controlled trial comparing the effects of twelve months’ oral supplementation with 12,000 IU, 24,000 or 48,000 IU vitamin D3each month on BMD at the hip in community dwelling older people._x000D_ _x000D_ Effects on plasma 25OHD, parathyroid hormone (PTH) levels and biochemical markers of bone turnover will also be evaluated. We will explore the plasma 25OHD level required to prevent a decrease in BMD over 12 months and evaluate the suppression of PTH and the biochemical markers of bone turnover and explore whether higher concentrations of serum 25OHD are associated with greater suppression of PTH and bone turnover.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL
Title: HERO: Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis, a randomised, double-blind, placebo-controlled trial
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is the most prevalent form of arthritis and an increasingly common problem in our aging society. Hand OA is highly prevalent and disabling, and current treatments are restricted by their duration, degree of efficacy and considerable associated toxicities. The identification of alternative treatment options, which will give good analgesic effect with few or acceptable associated side-effects, is therefore critical in enabling optimal management of people with hand OA. Recent imaging studies lend evidence to inflammation being a likely peripheral source of pain in OA. As such, targeting inflammation may prove an effective strategy in the search for improved OA analgesic therapies. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides such as rheumatoid arthritis and is widely used anecdotally as an analgesic treatment for OA. It is inexpensive, well-tolerated and suitable for the vast majority of patients. We aim to examine the hypothesis that treating patients with moderate to severe OA hand symptoms with hydroxychloroquine will be an effective and safe treatment to reduce people’s pain.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Age related tendon degeneration of the rotator cuff: The relationship between disease, pain and functional losses.
Funder: Arthritis Research UK

Abstract: The shoulder is the third most common site of musculoskeletal symptoms, and the major debilitation patients seek help for is pain. Full thickness rotator cuff tears (RCTs) have an estimated prevalence of between 7 and 27%, but studies have shown that not all of these are symptomatic. Many case series have been set in shoulder clinics and may have drawn false causality between RCTs and pain. We propose using a population-based study to test the association between RCTs pain, and functional losses._x000D_ _x000D_ _x000D_ _x000D_ This study will determine the epidemiology in an established community-based normal-population cohort. This is the first multidisciplinary assessment including a high-definition ultrasound, clinical examination, and the assessment of pain perceptions using quantitative-sensory-testing. This allows us to test associations between RCTs and symptoms, and identify risk factors for symptomatic tears. For this, we will investigate the role of altered central pain processing pathways as predictors for pain, and the role of generalised sarcopenia in the ability to compensate for a tear. Lastly, we will investigate the genetic tendencies towards pain in RCTs._x000D_ _x000D_ _x000D_ _x000D_ The study will improve understanding about the relationships between RCTs, pain and functional losses, allowing the effective tailoring of both surgical and alteranative non-surgical treatments to individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Characterisation of osteoarthritis phenotype in a unique multi-centre cohort of individuals with extremely high bone mass
Funder: Arthritis Research UK

Abstract: This studentship aims to improve understanding of the pathophysiology of OA, by exploring why OA risk is reduced in osteoporosis. This will be achieved by exploiting our unique cohort of over 300 individuals with high bone mass (HBM), following our recent preliminary findings that OA risk is increased in this group. The student will initially establish the phenotype and prevalence of OA in HBM cases, based on hand, hip and knee radiographs and clinical data which has recently been collected. Prevalence data will then be compared with controls recruited as part of our HBM study, and with the Chingford and Hertfordshire population based cohorts. Why OA risk is increased in HBM will then be determined by exploring the following questions based on detailed phenotypic and genotypic data which has also been collected: (i) Is the increased risk of OA in HBM explained by their higher levels of obesity and other features of the metabolic syndrome ? (ii) Is OA risk in HBM explained by the excess cortical and/or trabecular bone? (iii) Is OA risk in HBM explained by the underlying genetic mutation rather than by any associated bone or metabolic changes, suggesting an independent effect on articular cartilage?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Understanding the early life and environmental determinants of bone strength and structure using participants from the Hertfordshire Cohort Study
Funder: Arthritis Research UK

Abstract: Osteoporosis is a major public health problem through its association with fragility fracture. Previous work has suggested that early life factors play an important role in growth and maintenance of the adult skeleton, and that this may translate into altered fracture risk. This work represents a collaboration between the University of Southampton and the MRC Human Nutrition Research, Cambridge to offer a studentship that would use high resolution quantitative computed tomography in a highly regarded centre to perform virtual bone biopsy in a cohort characterised with regard to growth in early life and adult lifestyle. The study will also accrue normative data on rates of bone loss and changes in geometry and strength using peripheral quantitative computed tomography in one of the largest, best characterised cohorts studied to date. The study represents an excellent opportunity for training in epidemiological methods and study design; the proposed host centre has an excellent track record in this respect.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL