NIHRDataInsights/HRCSData huggingface dataset:
Title: A method to distinguish and isolate highly potent articular cartilage-derived stem cells
Funder: Arthritis Research UK

Abstract: Therapeutic treatments for articular cartilage repair are limited and where they exist, such as Autologous Chondrocyte Implantation (ACI), the procedures result in highly variable outcomes. We hypothesise that a major factor affecting the outcome of ACI and related cell-based therapies is the source of cells used to repair injured or diseased joints. We discovered that cartilage-derived stem cells from normal and osteoarthritic joints differentially express aldehyde dehydrogenase and that the level of expression directly correlates with cellular proliferative potential, senescence and telomere length, a marker for stem cell potency. Therefore, using a non-toxic fluorescent substrate for aldehyde dehydrogenase it will be possible, for the first time using fluorescence activated cell sorting, not only to unambiguously isolate cartilage specific stem cells but also to isolate a sub-fraction of these cells with the highest potential to repair lesions in joints. We can also track stem cell dynamics during disease and determine if changes in stem cell number or phenotype affect the course of disease. In addition, by performing comparative transcription analysis of normal and OA-derived stem cells we will be able to generate new hypotheses in an attempt to reverse or inhibit negative phenotypic changes that occur as a consequence of disease


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The clinical and cost effectiveness of steroid injection compared with night splints for carpal tunnel syndrome: a pragmatic randomised trial in primary care.
Funder: Arthritis Research UK

Abstract: Can we use medical imaging to identify OA patients who are likely to progress more quickly or who are more likely to benefit from a particular treatment?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: MUSCULOSKELETAL
Title: Acupuncture for Back Pain: Modifying the Psychological Determinants of Patient Outcomes
Funder: Arthritis Research UK

Abstract: My prospective cohort study of people with back pain receiving acupuncture has shown that higher scores on measures of outcome expectancy, treatment credibility and pain controllability at the start of treatment predict lower levels of disability at the end of treatment. By changing patients’ views about acupuncture and observing whether this causes lower disability levels post-treatment we can provide a stronger test of the importance of these psychological factors and improve clinical outcomes. The research proposed here will develop a means of encouraging people to have more positive beliefs about acupuncture that are nevertheless consistent with the scientific literature on acupuncture’s effectiveness. We will design and pilot-test a psychologically-informed webpage to address common concerns about acupuncture (will it hurt?), present information about its likely effects (will it work?), and allow people to explore the rationale underlying acupuncture for pain relief (how could it work?). An experiment will test whether the website can change beliefs about acupuncture in 176 participants with back pain. In the future, the webpage could be easily adapted for use in clinical trials (measuring the effect of the webpage on treatment outcomes) and/or hosted on a publicly available website (e.g. Arthritis Research UK).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Meniscal allograft transplantation and the prevention of osteoarthritis.
Funder: Arthritis Research UK

Abstract: The meniscus is a structure within the knee that has an important role in protecting the surface of the joint from impact. The menisci can be torn during sporting and other activities, which may cause locking and giving way of the knee. Partial meniscectomy, where the torn portion of the meniscus is removed, is the most common knee operation in the UK. It may cure the symptoms but severely reduces the ability of the meniscus to protect the joint from damage, leading to osteoarthritis (OA) of the knee._x000D_ This proposal concerns an alternative treatment for a torn meniscus. Meniscal allograft transplantation (MAT) is effective at reducing pain and is safe. However, there is little evidence as to whether MAT protects the knee from OA._x000D_ During the Fellowship I will 1. Perform a systematic review of the literature of the evidence for MAT and protection from OA. 2. Review the results of a large series of patients that have had MAT. 3. Design and deliver a pilot randomised trial of MAT versus standard treatment. 4. Use novel magnetic imaging techniques to determine the chondroprotective effect of MAT._x000D_ This research may help prevent OA of the knee in the future.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: The role of osteoarthritic subchondral bone in disease initiation, progression and therapy
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is characterised by chronic pain, disability and reduced quality of life; it confers a massive burden on health economies. Current therapy is symptomatic and modification of structural progression is a key goal. The subchondral bone has been demonstrated to be integral to both OA symptoms and structural progression. My supervisor has recently demonstrated that magnetic resonance imaging (MRI) whole-knee bone shape is a highly sensitive marker of disease progression in OA. This thesis will examine the role of subchondral bone in knee OA and employ both novel cohorts (NIH Osteoarthritis Initiative, a longitudinal MRI cohort) and novel quantitative imaging techniques (3D active shape modeling on MRI that gives high precision of measurement). Firstly in a 1500 person cohort with established knee OA, the relationship of bone shape to symptom and radiographic progression will be explored. Secondly, the role of bone at initiation of both symptoms and radiographic OA will be investigated in an at-risk 3500 person longitudinal cohort. Finally, a feasibility trial of the potent bisphosphonate, zoledronic acid, will be conducted with bone shape as the primary outcome, together with multi-tissue MRI assessment, to explore the concept of targeting subchondral bone for disease modification in OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Understanding the relationship between psychosocial impact of chronic joint pain and exercise to improve patient management: A synthesis of quantitative and qualitative research.
Funder: Arthritis Research UK

Abstract: There is a complex, relationship between chronic joint pain, physical function and psychosocial effects (anxiety, depression, self-confidence, health beliefs, behaviours, etc) - each affect and are affected by the others. We know exercise improves pain, physical and psychosocial effects, but how best to deliver exercise advice is unclear, which may waste time, effort and overlook the best way to treat people._x000D_ _x000D_ We want to improve chronic joint pain management by increasing awareness and understanding of the complex inter-relationship between pain, physical function and psychosocial effects. This will be achieved by summarising research evidence showing the impact of these complex relationships, and establish how to teach the value of exercise._x000D_ _x000D_ These findings will be used to describe the most effective ways of delivering exercise, to assist healthcare commissioners and clinicians in providing more effective programmes and encourage patients to accept and engage in these programmes.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: The Pain Garden: development and evaluation of an online educational tool to improve patients' understanding and provoke learning about the multidimensional nature of persistent pain.
Funder: Arthritis Research UK

Abstract: For many people with musculoskeletal conditions their lack of understanding of the multidimensionality of persistent pain is a significant barrier to managing their condition. This project aims to develop a unique online educational tool to facilitate that understanding._x000D_ _x000D_ The project will apply principles of data visualisation and metaphor to depict a person’s results from a pain questionnaire as an interactive animation of a garden. The questionnaire items (covering sensory, emotional and wellbeing factors) will be displayed as items of the garden. For example, the item “anger” will be represented by a computer-generated image of a tree with definable “angry” features that change with the item’s score. Led by the research team a data visualisation and animation company will build the tool in ongoing consultation with a group of six people with musculoskeletal pain. It will then be evaluated with thirty people with different painful musculoskeletal conditions and eight health professionals.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Understanding the impact of Degenerative Lumbar Disc Disease (DLDD) on function in people with and without low back pain
Funder: Arthritis Research UK

Abstract: Degenerative Lumbar Disc Disease (DLDD) is associated with disc, vertebral, ligamentous and joint changes. Although it is a common finding in older people the key causes remain poorly understood (Videman, 2010, Griffith, 2007), and what intrigues us in this study is that the presence of DLDD can cause severe and persistent low back pain in some people but no pain or indeed symptoms in others. We would like to explore why this happens by firstly looking to see if there are differences in the structure of the lumbar spine in terms of its shape and dimensions and in the size and quality of the supporting muscles in DLDD people with and without pain and also a normal control population. Then secondly, we want to look at the movement patterns not only of the lumbar spine but of the body as a whole with a particular emphasis on the pelvis and lower limbs to see if people with DLDD compensate and move differently using different body segments, thereby protecting and un-loading their lumbar spine. We will also account for demographic and psychosocial factors and explore their role in regards to the presentation or absence of pain.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The Effect of Spironolactone on Pain in Older People with Osteoarthritis (SPIR-OA)
Funder: Arthritis Research UK

Abstract: This pilot study will obtain preliminary evidence on which to base sample size calculations for a future trial of whether spironolactone (an aldosterone blocker) reduces knee pain in older people with symptomatic OA knee when given in addition to usual analgesia. Aldosterone is know to be pro-inflammatory, and spironolactone suppresses cytokine production in chronic arthritis. This application builds on previous work by the applicants showing that spironolactone significantly improved quality of life (particularly pain) in frail older people. We will randomise 80 people (aged 70 years or over) with well defined OA knee to 25mg spironolactone daily or to matching placebo for 12 weeks. The primary outcome is the between group difference in change in WOMAC pain subscore at 12 weeks. Secondary outcomes are the WOMAC stiffness and physical function subscales and health related quality of life (EQ-5D). Morning cortisol levels will be measured to assess the effect of mineralocorticoid receptor blockade on glucocorticoid levels, which may mediate the anti-inflammatory effect of spironolactone; and urinary CTX-II, and serum matrix metalloproteinase-3 (MMP-3) will be measured as biomarkers as both are sensitive to the effects of pharmacological interventions for osteoarthritis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Functional analysis of the hip osteoarthritis susceptibility locus at chromosome 6q13-q14.1
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) susceptibility loci are now emerging from genome-wide association scans with the arcOGEN study, funded by Arthritis Research UK, proving to be particularly effective based on its large sample size and its focus on severe end-stage disease. The most compelling joint-specific association signal detected by arcOGEN is to SNP rs9350591 on chromosome 6q13-q14.1. This association has a p-value of 2.42x10-9 and an odds ratio of 1.18 in female and male patients with hip-OA. The association signal encompasses seven genes, none of which have previously been implicated in OA etiology. Six of the genes are expressed in joint tissues and none of these contain an amino-acid substitution that could account for the association. Our hypothesis therefore is that this hip-OA association is accounted for by a cis-acting regulatory polymorphism that modulates the expression in joint tissues of one of the genes from within the 6q13-q14.1 locus. To test this hypothesis we shall perform a number of experiments, including the use of patient joint tissues, to identify and characterize cis-acting polymorphic elements that correlate with the association signal. By so doing we shall be able to pinpoint the gene from within the locus that accounts for the association.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Can hip DXA scans be used to identify genetic determinants of hip shape and osteoarthritis? Proposal for a proof-of-concept study
Funder: Arthritis Research UK

Abstract: Mutations resulting in hip dysplasia represent rare but important causes of hip osteoarthritis (OA). Commoner forms of genetic variation, with more subtle effects hip shape, may also contribute to hip OA. However, though several components of hip shape are associated with hip OA, rather than a causal role, these relationships may reflect altered hip modeling secondary to OA. The present proposal is intended to identify the major common genetic determinants of hip shape, thereby enabling (i) Mendelian Randomisation studies to examine causal pathways between hip shape and OA, and, in the case of shape parameters found to play a causal role, (ii) the identification of novel genetic risk factors for OA acting through specific alterations in hip shape. Genetic markers of hip shape will be identified by performing genome-wide association studies followed by meta-analysis, using hip shape parameters generated from hip DXA scans as part of this study. Hip DXA scans, matched to genome-wide genetic data, will be available in approximately 38,000 individuals from 12 population-based cohorts. Causal pathways between hip shape and OA will subsequently be explored using genetic predictors of hip shape identified in these analyses, in a large independent collection of OA cases and controls (arcOGEN).


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Sulforaphane, a dietary isothiocyanate with chondroprotective properties (extension)
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is a degenerative joint disease characterised by degradation of articular cartilage where there is a lack of effective drugs. We have focused on a dietary isothiocyanate, sulforaphane (SFN), from broccoli and other cruciferous vegetables. We had shown SFN abrogates interleukin-1-induced metalloproteinase expression in human articular chondrocytes (HAC); blocks cartilage breakdown in a bovine cartilage model and spontaneous matrix loss in human OA cartilage explants. In two years Arthritis Research UK funding, we have demonstrated: (i) SFN abrogates OA in the murine DMM (destabilization of the medial meniscus) model; (ii) SFN acts in chondrocytes independently of Nrf2, HDACs, alters response of MAP kinases, but blocks action of NFκB; (iii) the relative efficacy of a range of dietary isothiocyanates._x000D_ In this application for a further year, we aim to: (i) underscore mechanism of action of SFN, comparing those genes regulated in vitro (primary HACs and tissue explants) and in vivo (the murine DMM model); (ii) use these data to ascertain the action of SFN as an NFκB inhibitor and/or identify other relevant pathways (iii) use the structure-activity relationship we have uncovered to test synthetic isothiocyanates in vitro._x000D_ This application will provide evidence to move this study towards a human trial.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: The role of the inter-fascicular matrix in mediating tendon fatigue resistance: Do age related changes lead to tendinopathy?
Funder: Arthritis Research UK

Abstract: While tendinopathy is common and increases with age, current treatments are limited and ineffective. Development of new treatment strategies is challenging, as the factors predisposing specific tendons to tendinopathy are poorly understood. However, we have evidence suggesting that the interfascicular matrix (IFM) is critical for facilitating tendon extension and recoil, and thus maintaining tendon fatigue resistance and health. This is particularly important in energy storing tendons, which experience high strains during use and are prone to tendinopathy. Further, we have evidence that IFM properties are altered in aged individuals, a group in which tendinopathy is widespread. We therefore hypothesise that energy storing tendons have a specialised IFM, enabling them to sustain large repetitive strains without damage. A less specialised IFM or age-related deterioration reduces IFM extensibility and elasticity, predisposing certain tendons to chronic tendinopathy. We will investigate IFM structure in different tendon types from different aged individuals, and correlate this with IFM and tendon fatigue and failure properties. This will allow us to identify the IFM components key in maintaining tendon function and preventing tendinopathy, and determine why specific tendons and individuals are prone to injury. This understanding will aid the development of novel repair and rehabilitation strategies for tendinopathy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The Outcomes in Ankle Replacement Study (OARS): A study of patient reported outcome following total ankle replacement based on data from the National Joint Registry for England and Wales
Funder: Arthritis Research UK

Abstract: Total Ankle Replacement (TAR) is used increasingly as a real alternative to fusion of the ankle in the management of end stage ankle joint osteoarthritis, a condition that affects more than 29,000 patients per year in the UK. However, in common with the other forms of major joint replacement, there is wide variation in surgical practice. There is a dearth of evidence supporting the optimal use of TAR. Few studies include patient reported measures of outcome (PROMs). The England and Wales National Joint Register (NJR) has recorded TARs since April 2010, and currently includes details on implant type and surgical technique for 500 operations annually. Using the NJR as a platform, the current proposal will supplement these data with validated PROMs recorded during the first year following surgery in 600 consecutively registered patients. Data will include clinical and radiological disease severity pre-operatively, and post-operative surgical outcomes and complications. This will be the first comprehensive register-based assessment of PROMs following TAR. The results will facilitate the rational use of TAR among patients with end stage ankle disease, and inform future clinical trials comparing different TAR techniques as well as other forms of management.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: The role of histone deacetylase 3 in chondrogenesis and osteoarthritis
Funder: Arthritis Research UK

Abstract: Cartilage loss is the archetypical feature of osteoarthritis (OA), essentially caused by type II collagen degradation mediated by matrix metalloproteinase-13 (MMP13), established since MMP13-null mice show protection of cartilage loss in the destabilisation of the medial meniscus (DMM) model of OA. Our published work and preliminary data show that a class of molecules, histone deacetylase (HDAC) inhibitors can prevent MMP13 expression, collagen loss and now importantly OA-like cartilage erosions in the DMM model. Furthermore, this is via specific inhibition of a member of the class I HDACs, HDAC3 in vitro. Our key goals here are: to assess skeletal development and induced DMM-OA using cartilage-specific Hdac3-null mice, since germ-line depletion of Hdac3 is lethal. Using an in vitro model of chondrogenesis and human articular chondrocytes (HAC) the consequences of HDAC3-depletion will be determined and differentially regulated genes identified. The consequences upon chromatin of HDAC-depletion in HAC both specifically at the MMP13 and globally will be analysed using chromatin immunoprecipitation (ChIP) and ChIP-seq respectively. Together, these data will confirm the importance of HDAC3 in cartilage, chondrocytes and OA, and validate this gene and the pathways it regulates as potential therapeutic targets to prevent or slow the cartilage loss associated with OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: How do the interactions of TSG-6 with BMPs and RANKL contribute to its protective effects in cartilage and bone?
Funder: Arthritis Research UK

Abstract: An important goal in the treatment of diseases such as OA and RA is the prevention and/or reversal of the joint damage that occurs due to dysregulated cartilage and bone turnover. TSG-6 represents an attractive therapeutic target, given that it is chondroprotective and anti-resorptive and acts as an endogenous protector of joint function during inflammation; these activities are likely mediated via multiple mechanisms This project is focussed on determining how the interactions of TSG-6 with RANKL (that drives osteoclast formation/activation) and BMP-2 and BMP-7 (that promote osteoblastogenesis and cartilage formation/repair) might contribute to its protective effects. In particular, we are interested in how TSG-6 function is controlled at the cartilage/bone interface. An initial aim is to map the binding sites for BMP-2, BMP-7 and RANKL on TSG-6 and determine how these interactions are co-ordinated and/or differentially regulated. This will allow identification of TSG-6 mutants with selectively modified ligand-binding properties, where their characterisation, using in vitro assays of cartilage degradation and bone formation/breakdown, will provide important insights into the mechanisms by which TSG-6 modulates these processes. This studentship will provide excellent training in a wide range of state-of-the-art techniques and facilitate the development of novel therapies for arthritic disease, e.g. OA.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL