NIHRDataInsights/HRCSData huggingface dataset:
Title: Dissecting the complex roles of peripheral sensory afferent input and supraspinal influences in osteoarthritic pain
Funder: Arthritis Research UK

Abstract: Pain in osteoarthritis (OA) is severe and debilitating. Structural changes within the joint are poorly correlated to OA pain, sugesting that changes in the central processing of sensory inputs contributes to pain. We hypothesise that early in OA increased pain responses are predominantly mediated by altered sensory afferent activity, however once established, changes in the spinal and supraspinal processing of pain maintain the altered sensory processing and the chronic pain experienced. We aim to investigate the changing contributions of peripheral and supraspinal pain centres in the establishment and maintenance of pain in animal models of OA. Firstly, we will selectively inactivate joint afferent fibres at selected timepoints in two models of OA and will determine how this impacts upon the establishment of pain behaviours; altered weight bearing and mechanical allodynia. Next we will inactivate a key supraspinal site, which has a well described role in the facilitation of pain, in these models and investigate the impact upon the same behavioural parameters and some key electrophysiological markers of central sensitisation. This study will establish the timecourse, interactions and anatomical site of key neurological components that are essential for establishing and maintaining OA pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Human tenocyte metabolism under physiological and pathological loading conditions
Funder: Arthritis Research UK

Abstract: Human tendons are increasingly prone to tendinopathy, a painful and debilitating condition, preventing use of the affected region. The aetiology of tendinopathy is poorly understood, but it is thought to occur in response to tissue overloading. This study hypothesizes that tendinopathy develops in response to tendon microdamage, which initiates a catabolic response from the tenocytes. In order to investigate tenocyte metabolism, a novel fibre composite material has been developed, which more closely matches the in situ tenocyte strain environment, notably replicating the shear loading seen at a cell level. Isolated cells seeded within the model will be subjected to a range of physiological and pathological strain conditions in order to investigate the mechanical cues governing matrix anabolism and catabolism, hypothesizing that excess shear strain on tenocytes initiates matrix breakdown. Data will provide insights into the optimal strain regimes to promote tendon repair and lead to a range of potential evidenced-based therapies to improve rehabilitation of injured patients. Furthermore, this novel material will provide the potential for numerous future studies in tissue engineering and drug therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The delivery of a layered and culturally appropriate electronic educational resource for ethnic minorities
Funder: Arthritis Research UK

Abstract: There is a well recognised need to provide ethnic minority patients with suitable health educational resources. This project aims to provide a culturally appropriate and layered electronic educational resource package for people from ethnic minority groups that can be delivered within a community setting. It will test user acceptability whilst also addressing, using a mixed methods approach, the hypothesis that educational resources delivered in this manner improve health knowledge and awareness._x000D_ _x000D_ The outcomes of the project will not only provide valuable lessons to empower ethnic minority communities, but will also benefit all patients and members of the public generally through layering and stratification of the educational resources, thus enabling user centredness through user control of desired format and depth of knowledge. In addition, the study will provide pilot data for a future randomised controlled trial of the effect of this resource and approach on compliance/concordance in osteomalacia.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Does exogenous Wnt16 improve the outcome of osteoarthritis in vivo?
Funder: Arthritis Research UK

Abstract: Wnt16, a growth factor involved in joint formation during embryogenesis, is re-expressed in adult joints after injury and in the early phases of osteoarthritis. We showed that wnt16 deficient mice are more susceptible to experimental osteoarthritis than wild type littermates. Therefore Wnt16 has a protective effect on cartilage. In this application we propose to investigate the molecular mechanism of this chondroprotective effect and whether exogenous administration of Wnt16 is chondroprotective in vivo. First, we will characterise at the molecular level the phenotype of Wnt16-/- mice in an experimental osteoarthritis model and in vitro. Second, we will investigate which Wnt signal transduction pathway(s) mediates the effects of Wnt16 on the chondrocyte phenotype. Third we will investigate the therapeutic potential of Wnt16 delivery in an experimental osteoarthritis model in mice. _x000D_ _x000D_ The identification of a specific molecule, naturally involved in the homeostasis of the adult articular cartilage is an unprecedented opportunity for the identification of a disease-modifying therapy for a leading cause of disability worldwide such as osteoarthritis.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Protection of articular chondrocytes against trauma in vivo by hyperosmolar solutions
Funder: Arthritis Research UK

Abstract: During routine surgical orthopaedic/articular procedures, cartilage can be exposed to a range of injurious mechanical perturbations caused by accident or design. These can damage healthy cartilage and other joint tissues making it more susceptible to degeneration thereby increasing the likelihood of osteoarthritis. Our results suggest that the irrigation solutions currently in use (e.g. saline) are sub-optimal and cause cartilage cells to be far more sensitive to mechanical injury. Furthermore, simply by increasing the osmolarity, we can markedly reduce the cell death associated with a carefully-controlled injury from a single scalpel cut. This modified solution could therefore be of clinical benefit and here we wish to determine if this protective effect can be demonstrated in an in vivo animal model. Firstly, we must test if injection of this protective solution into an animal joint initiates a significant inflammatory effect compared to saline. Secondly, we will use a reproducible in vivo rat model of cartilage injury resulting from a single cut with a scalpel blade for baseline data. Thirdly, we will compare the cutting injury to cartilage irrigated with either saline or the protective solution. These results are required before it would be possible to introduce this protective solution into surgical practice.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: MUSCULOSKELETAL
Title: Assessment of Fast Field Cycling Mr.I for the imaging of articular cartilage and osteoarthritis
Funder: Arthritis Research UK

Abstract: Fast Field Cycling Magnetic Resonance Imaging (FFC-Mr.I) is a novel Mr.I technique that can measure protein concentrations in human tissue. It is known that one of the early changes in osteoarthritis is a reduction in glycosaminoglycans concentration in the articular cartilage. Pilot work in our institution has shown significant differences in protein concentrations between osteoarthritic and normal cartilage using FFC-NMr.. _x000D_ _x000D_ We now wish to examine further the relationship between FFC- Mr.I measurements and absolute measurement of cartilage composition in the hip and knee in an in vitro experiment, prior to potential clinical imaging using this technique. Cartilage will be obtained from patients undergoing joint replacement for osteoarthritis of the hip or knee (osteoarthritic cartilage) and patients undergoing amputation or operation for hip fracture (normal cartilage)_x000D_ _x000D_ Our key goals are:_x000D_ _x000D_ To examine the relationship between FFC-Mr.I measurements of normal and osteoarthritic articular cartilage and_x000D_ _x000D_ _x000D_ Laboratory measurement of glycosaminoglycans, collagen and total protein concentration. _x000D_ Histological grading of osteoarthritis._x000D_ Standard Mr.I measurement of water content and structure_x000D_ _x000D_ To compare FFC relaxometry (FFC-NMr.) results (core samples) with “whole body” FFC-Mr.I scanner measurements (whole joint samples).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Regulation of Bone Metabolism by neuronal NOS
Funder: Arthritis Research UK

Abstract: We have found in pilot experiments that nNOS KO mice have increased bone loss after ovariectomy, and increased gain of bone volume after treatment with oestrogen. These data indicate an important role for nNOS in regulating the effects of estrogen on bone, and identifies nNOS as a target for the development of novel bone anabolic therapies. We propose to study the response to changes in estrogen levels in detail by extending our pilot experiments with a detailed analysis of bone turnover. It is unclear whether the effects of nNOS on bone metabolism are due to direct effects in bone cells. To address this we will study bone metabolism in animals where nNOS has been deleted in cells of the osteoblast lineage using the Cre-LoxP system. Recent data has shown that nNOS is the main NOS isoform expressed in bone cells, and that nNOS may be the major source of NO after mechanical loading. We will therefore perform in vivo loading studies to assess whether nNOS regulates mechanical adaptation of bone architecture.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Acupuncture, Alexander technique lessons and usual care for patients with chronic neck pain: a randomised controlled trial to evaluate effectiveness, cost effectiveness, acceptability and safety.
Funder: Arthritis Research UK

Abstract: Chronic neck pain is a common condition in the adult population. As well as being painful and disabling it is associated with significant costs to the individual, their families, the NHS, and society in general due to reduced productivity and social engagement. More research is needed to evaluate interventions aiming to facilitate beneficial long-term change. While patients commonly self refer to acupuncture and Alexander Technique lessons, evidence from the literature, while promising, is too uncertain for routine referral. We propose to evaluate these interventions in a rigorously designed pragmatic trial (with an embedded qualitative study), reflecting what might happen in usual practice. This will provide robust evidence on whether there are: significant worthwhile clinical benefits to patients; economic benefits demonstrating value for money; and sufficient levels of acceptability and safety. In the proposed trial 450 patients will be randomised in equal proportions to acupuncture, Alexander Technique lessons or usual GP care alone. The researchers involved in this study have considerable expertise in running large trials of interventions for musculoskeletal conditions including chronic neck pain and will conduct the trial at the NIHR accredited York Trials Unit, which has a track record of disseminating findings that translate into improved clinical practice.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: MUSCULOSKELETAL
Title: Is Arthroscopic Sub-Acromial Decompression (ASAD) More Effective Than Arthroscopy Only (AO) For Shoulder Pain?
Funder: Arthritis Research UK

Abstract: Sub-acromial pain is a common condition of the shoulder joint causing dysfunction. Arthroscopic Sub-Acromial Decompression (ASAD) is an increasingly popular treatment option but it remains unknown whether surgical removal of bone spurs from the acromion is necessary for successful outcome. ASAD may provide no more benefit than investigative arthroscopy alone (no spur removal). This randomised placebo controlled study aims to determine whether arthroscopic intervention is effective in treating this painful shoulder condition and, if so, what part of this is due to removal of bone spurs from the acromion._x000D_ _x000D_ Patients will be randomised to 1) arthroscopic sub-acromial decompression (ASAD) 2) investigative shoulder arthroscopy or 3) a no treatment control group. Comparison between the two surgical groups will provide evidence for the efficacy of ASAD over arthroscopy alone thereby delineating the mechanism for therapeutic effect. Comparison of the surgical groups against the control group will provide evidence for the efficacy of arthroscopic surgical intervention, in general, for sub-acromial pain._x000D_ _x000D_ The primary outcome will be the Oxford Shoulder Score at 6 months. 300 patients will be recruited from 7 different centres. In providing evidence of both efficacy and mechanism the study will substantially contribute to the care of patients with shoulder pain


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Role of thyroid hormone receptor alpha in osteoarthritis susceptibility and prevention
Funder: Arthritis Research UK

Abstract: 8.5 million UK individuals suffer from osteoarthritis, resulting in a huge burden to society. Patients are asymptomatic until significant cartilage damage has occurred, but unfortunately there are no drugs that prevent or delay disease progression. Nevertheless, two genome wide association studies now indicate that regulation of thyroid hormone (T3) action is important in susceptibility to osteoarthritis. We previously defined TRα as the final mediator of T3 action in cartilage, thus highlighting its potential as a therapeutic target in osteoarthritis. We hypothesize that deletion or inhibition of TRα in adult articular cartilage decreases susceptibility to osteoarthritis and delays disease progression. We have thus developed suitable animal models and identified a specific inhibitor of TRα to investigate this hypothesis. The goals of these studies are to determine whether (i) deletion of TRα in chondrocytes and (ii) treatment with a TRα antagonist delay the onset and progression of osteoarthritis. TRα will be deleted in adult chondrocytes using TRαflox/flox and tamoxifen-inducible Agc1-creER mice, or inhibited using the antagonist dronedarone. Their effects on the onset and progression of osteoarthritis will be determined in a well-established surgical model of disease. These studies will establish the role of TRα antagonists in the treatment of osteoarthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: FSTL3/TGFb family ligand signalling as a driver of OA progression
Funder: Arthritis Research UK

Abstract: Factors dictating osteoarthritis (OA) progression, once initiated, remain enigmatic. During this fellowship I will test the hypothesis that follistatin-like 3, a natural inhibitor of activin/TGFβ family-members, selectively limits OA progression by regulating SMAD signalling. Testing this, is made feasible by my characterisation of a new loading model that can discriminate between initiation and progression phases of OA, and by additional pilot data showing that mice lacking FSTL3 develop OA only upon ageing. My proposed studies will establish whether OA progression is selectively accelerated, and regulated by particular chondrocyte behaviours and pathways, in FSTL3-deficient mice, and whether this progression phase is defined by specific SMAD pathway modulation. This will be achieved using murine models of mechanical instability and trauma, and by in vitro studies focussed on modified phenotype and response to anabolic/catabolic factors in primary chondrocytes and articular cartilage explants from normal and FSTL3-deficient mice. Ultimately, my studies will define whether FSTL3 modifies SMAD activity to selectively control the rate of OA progression. This will open possibilities for using FSTL3 or the cellular mechanisms through which it acts, as a target for slowing OA progression and may identify a new marker for pinpointing patients at greatest risk of rapid joint deterioration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The Role of microRNAs in Cartilage Function and Joint Repair
Funder: Arthritis Research UK

Abstract: MicroRNAs are regulators of gene expression critical for development and tissue homeostasis; their dysregulation being implicated in various diseases. We will test whether manipulation of these regulators can stimulate repair of damaged and osteoarthritic joints. A novel discovery in our laboratory was made by identifying a tissue-specific microRNA (miR-675) in human cartilage which regulates type II collagen - loss of which is a hallmark of osteoarthritis. We will now uncover the role of miR-675 in vivo through the generation of genetically modified mice. Mechanism of action will be probed by identifying endogenous microRNA targets using a RIP-Seq approach. Finally, experiments in mice using models of osteoarthritis and genetically-modified strains will establish whether microRNAs can be used to reprogramme cartilage in the early stages of arthritis and assess whether repair mechanisms can be promoted. We strongly believe this work will inform future development of clinical trials to directly assess therapeutic benefit in patients.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Genetic and Environmental Determinants of Paget's Disease
Funder: Arthritis Research UK

Abstract: Paget’s disease of bone (PDB) is a common skeletal disorder. Genetic and enviromental factors both play a role in PDB but most of the causal genetic variants remain to be identified and the environmental triggers are poorly understood. We have recently identified seven loci that predispose to PDB by genome wide association, have developed an animal model for the disease and have gained evidence to suggest that PDB patients may have an altered immune response to viral infection. Given this background, the present programme will:_x000D_ _x000D_ _x000D_ Identify the functional genetic variants that predispose to PDB and define the mechanisms by which they regulate bone metabolism. _x000D_ Develop genetic markers for PDB to identify people at risk of developing the disease and of complications _x000D_ Investigate the hypothesis that inherited abnormalities in the immune response to infection is related to the pathogenesis and severity of PDB_x000D_ Examine the role of nutrition and mechanical loading as triggers for the disease in an animal model._x000D_ _x000D_ Taken together, the studies will improved our understanding of why PDB occurs and identify new markers for disease susceptibility and complications that could be coupled to early therapeutic intervention in selected high risk patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Molecular pathology of acromelic dysplasias associated with FBN1 mutations
Funder: Arthritis Research UK

Abstract: Weill-Marchesani syndrome (WMS), stiff skin syndrome (SSS), geleophysic dysplasia and acromicric dysplasia are a newly described group of diseases caused by FBN1 mutations. In marked contrast to the tall stature and cardiovascular features often seen in Marfan syndrome (MFS) patients, these newer disorders result in short stature, joint stiffness and skin thickening, and are caused by mutations affecting specific regions of fibrillin-1. Diseases associated with FBN1 mutations generally cause TGFβ dysregulation, but those associated with WMS, SSS and the geleophysic and acromicric dysplasias also cause excess matrix production with phenotypes resembling scleroderma. Mutations in the genes for ADAMTS10 and ADAMTSL2 also cause WMS and geleophysic dysplasia, suggesting a strong functional overlap between these proteins and fibrillin-1. Using structural biology, protein chemistry and cell biology techniques, we will investigate the effects of these newly described mutations on the structure of fibrillin-1 and its interactions with cell and matrix components such as ADAMTS10 and ADAMTSL2. Our aim is to use the genotype-phenotype correlations provided by these newly described disorders as a platform to give new mechanistic insights into matrix regulation. This will increase our understanding of a wider group of related diseases, including scleroderma, which have matrix regulatory defects.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Musculoskeletal health and extended working life
Funder: Arthritis Research UK

Abstract: The need to keep the ageing workforce economically active has encouraged policies to extend working lives. Work may carry some health benefits, but for those with common musculoskeletal disorders of ageing (MSDs) the position seems more finely balanced, since they may struggle to cope with physically demanding work and be at heightened risk of occupational injury. However, involuntary job loss may precipitate psychological ill-health._x000D_ _x000D_ To assess (i) the impact of MSDs on work capability and employment status at older ages, (ii) the social, occupational, personal, and medical co-factors that modify vocational outcomes, (iii) the impact of job loss on subsequent health, and (iv) the risk of workplace injury in patients with MSDs, we will recruit 6,000 50-64 year-olds from the General Practice Research Database (GPRD). Participants will complete baseline and follow-up questionnaires over 3 years. Data on MSDs and other diagnoses will come from their GPRD-linked medical records; and data on employment (including job change), working conditions, and social and personal co-factors from questionnaire responses. Changes in health (e.g. new illnesses/treatments, hospital referrals) will be logged. Multi-level modelling will be used to assess the effect of MSDs on employment status and the role of other risk factors as effect modifiers.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MUSCULOSKELETAL
Title: Functional analysis of the osteoarthritis susceptibility locus at chromosome 3p21.1
Funder: Arthritis Research UK

Abstract: Robust osteoarthritis (OA) susceptibility loci are now emerging from genome-wide association scans. The arcOGEN study, funded by Arthritis Research UK, has proved to be particularly effective, based on its large sample size of over 7,400 cases and its focus on severe end-stage disease. Five genome-wide significant signals have so far emerged from arcOGEN with a signal at chromosome 3p21.1 being particularly compelling, with a p-value <1.2x10-10 at two SNPs in complete linkage disequilibrium (r2=1.0); rs6976 within GLT8D1 and rs11177 within GLN3._x000D_ _x000D_ Our hypothesis is that this 3p21.1 OA association signal is accounted for by cis-acting regulatory variants. We already have pilot data revealing that genotype at rs11177 correlates with allelic expression imbalance (AEI) of GNL3 in OA joint tissues. In this application we propose to test the other genes from within the 3p21.1 associated signal for cis-acting regulatory variants and to then functionally characterize the causal SNP(s) and their relevant genes for roles in OA etiology.


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