NIHRDataInsights/HRCSData huggingface dataset:
Title: The Role of miR-145 in Osteoarthritis and Repair
Funder: Arthritis Research UK

Abstract: MicroRNAs are regulators of gene expression critical for normal tissue function, their dysregulation being implicated in many diseases. We have discovered a specific microRNA (miR-145) in human articular chondrocytes which targets (inhibits) SOX9 – a master regulator gene essential for production and maintenance of cartilage. Our joints have a limited capacity for repair leading to increased susceptibility to various diseases, most notably osteoarthritis. Ways to offset these changes and reprogramme the cartilage to induce a repair response are needed. We hypothesise that inhibition of SOX9-targeting miR-145 will exert such chondroprotective effects. To this end we will fully uncover whether miR-145 is a modulator of osteoarthritis progression and joint repair through testing of miR-145 knock-out mice in specific injury and osteoarthritis mouse models. The functional importance of novel targets of miR-145 recently identified in our lab using RIP-Seq technology will also be fully investigated. Finally, the expression of miR-145 (and its targets) in topographically distinct tissue sites with varying grades of osteoarthritis will be uncovered. Integration of both aspects of the project (mouse and human studies) is necessary before we can translate our work to full therapeutic advantage.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Development and clinical validation of four novel biomarker assays for osteoarthritis
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is a common disease with substantial morbidity. Diagnosis using x-rays or MRI occurs when there is already irreparable damage to the joints. OA-specific biomarkers would enable early diagnosis and more effective management but existing biomarkers, mostly based on cartilage breakdown products, have poor specificity and sensitivity._x000D_ _x000D_ Our recent proteomic studies discovered four new serum markers which are not cartilage breakdown products. Three have been purified, biochemically-characterised and identified by mass spectrometry as: V65 vitronectin, complement C3f, and connective tissue-activating peptide III (CTAPIII). We have synthesised 0.3 mg of each and hypothesise that they will be more sensitive and specific for detecting OA and monitoring progression._x000D_ _x000D_ This study will develop ELISA-based assays for these novel biomarkers, and validate them in already collected serum samples from OA cohorts, healthy controls and other disease groups. Subsequently, diagnostic and prognostic value will be examined using stored samples from the USA NIH OA Sample Repository from 342 patients with OA and 342 matched controls subjects. We will also assess the ability to predict treatment outcomes using samples from a published placebo-controlled trial of Doxycycline._x000D_ _x000D_ The sample sizes are based on our extensive pilot data and the main study requires no new sample collection.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Subchondral bone sclerosis in OA is driven by defective mineralisation and osteocyte formation
Funder: Arthritis Research UK

Abstract: Modified subchondral bone (SCB) modelling and thickening are hallmarks of osteoarthritis (OA) and unquestionably contribute to OA pathogenesis. Currently, there are no known ways to restrict increases in SCB mass. This proposal will test whether SCB thickening in OA can be restricted by promoting E11 protein stability to drive osteocyte formation (osteocytogenesis) and sclerostin-mediated inhibition of bone formation. This hypothesis stems from our pilot data revealing that osteocyte formation is triggered by matrix mineralisation in a pathway reliant on the expression and stabilisation of E11 protein. Using hypomineralisation murine models (phospho1-/-) and human osteoblasts our first goal will determine if matrix mineralisation drives E11 expression and osteocyte formation. The critical requirement for E11 expression to drive osteocytogenesis will be confirmed by studying mice harbouring an osteoblast deletion of E11. Furthermore, we will determine the post-translational mechanisms controlling osteocyte E11 protein stability and whether these can be targeted to accelerate osteocytogenesis. Finally, OA-like trauma will be induced by non-invasive loading to determine if SCB changes are characterised by aberrant mineralisation and disrupted osteocytogenesis and E11 expression. This proposal will identify a novel means of selectively minimising increases in SCB mass to slow joint deterioration and prolong life quality in OA patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: A new approach to knee OA: stratifying patients into different subsets based on active gene pathways
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is a major joint disease, which currently lacks effective treatment. It is a complex disease and whereas in the past it was considered as a single condition, we now have evidence that cartilage damage, a major feature in knee OA, is driven by different mechanisms in different patients. Our previous data show that gene expression profiles for type II and type I collagen in OA cartilage segregates patients into 4 groups. This gives us the opportunity to stratify knee OA into subsets of patients which may benefit from different targetted treatments. We will achieve this stratification with a systems biology approach using deep sequencing. We will characterise and analyse expression profiles amongst samples of cartilage taken from joint replacement patients and compare with healthy age-matched controls. We will stratify the expression profiles in two ways, a) based on collagen gene expression and b) using broad holistic criteria, to identify subsets based on other novel differences in chondrocyte metabolism that will be revealed by the systems analyses. The demostration that stratification produces robust patient subgroups with potentially different and targetted treatment needs would be a major step forwards developing personalised approaches to OA management and therapy


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Learning to perform surgery for arthritis on cadavers: can it lead to better surgeons and safer patients?
Funder: Arthritis Research UK

Abstract: 1 in 6 people in the UK suffers from some form of arthritis1. Many of these people will require the services of an orthopaedic surgeon for joint replacement (arthroplasty) or joint realignment (osteotomy) surgery. It is of paramount importance that orthopaedic surgeons-in-training receive the highest quality training in surgical skills in order to deliver the best outcomes for their patients._x000D_ _x000D_ There are several potential threats to the quality of surgical training, including reduced trainee working hours, less case-load exposure in the operating theatre and shortened specialist training programmes. In view of this the Department of Health has recently highlighted the urgent need to investigate the role of simulation as a training adjunct for surgical trainees._x000D_ _x000D_ This is a novel prospective, educational cohort study investigating cadaveric simulation training (CST) as a high-fidelity surgical training tool._x000D_ _x000D_ Objectives;_x000D_ _x000D_ 1) Measure the early surgical skill acquisition trajectory of junior surgical trainees in CST-trained and standard-trained cohorts_x000D_ _x000D_ 2) Characterize skill retention following CST intervention_x000D_ _x000D_ 3) Determine trainee and trainers’ perspectives on the experience of CST_x000D_ _x000D_ 4) Explore the role of CST becoming formally integrated into Trauma & Orthopaedic Surgical training and ultimately inform future curriculum design.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL
Title: Understanding Failure in Unicompartmental Knee Replacement
Funder: Arthritis Research UK

Abstract: Unicompartmental Knee Replacement (UKR) is an alternative to Total Knee Replacement (TKR) in end-stage osteoarthritis. By replacing only the affected parts of the knee, it preserves the remaining joint surfaces and ligamentous structures, restoring pre-disease kinematics. UKR has advantages over TKR including shorter hospital stays, a faster return to work, superior cost-effectiveness and lower perioperative morbidity and mortality. However, whilst published series demonstrate excellent long-term implant survival, National Joint Registries (NJRs) demonstrate an unacceptably high revision rate for UKR, with the majority of failures being by aseptic loosening. _x000D_ _x000D_ The aim of this study is to determine factors associated with the high revision rate in UKR and to explore interventions to address these factors. These will involve study of factors concerning the patient (the influence of patient selection), the surgeon (the influence of surgical experience), and the implant itself (particularly bone-implant fixation). The study has three components: an epidemiological study of 500,000 knee replacements from the NJR for England and Wales, to determine patient and surgical factors associated with revision in TKR and UKR; biomechanical studies of the bone-implant interface in UKR; and clinical studies of a new, cementless UKR, designed to address the commonest cause of failure, aseptic loosening.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Does P2X7 receptor signalling control extracellular TG2 activity linked to osteoarthritic changes in cartilage?
Funder: Arthritis Research UK

Abstract: Aberrant transglutaminase 2 (TG2) activity has been implicated in the pathogenesis of both degenerative and inflammatory joint disease although distinct molecular mechanisms are involved. However, a shared feature is the abundant release of TG2 into the extracellular space that can promote chondrocyte hypertrophy, cartilage calcification and generate neo-epitopes that trigger autoimmunity._x000D_ _x000D_ _x000D_ _x000D_ TG2 is a non-conventionally exported protein and the mechanism of release has been elusive. Using a cell model, I have shown for the first time that purinergic signalling (P2X7 receptor activation) induces rapid export of TG2. The P2X7 receptor is a key sensor of tissue injury and is part of innate immunity. During joint loading ATP can also be released from chondrocytes and acts locally on purinergic receptors. We hypothesize that purinergic signalling has a central role in TG2 externalization in the context of joint disease._x000D_ _x000D_ _x000D_ _x000D_ The purpose of this study is to investigate whether P2X7 receptor activation in response to normal/abnormal mechanical loading is sufficient to induce TG2 externalization in cartilage or whether the presence of inflammatory mediators is an additional pre-requisite. Furthermore, we want to investigate whether P2X7 receptor-mediated TG2 release and down-stream reactions associated with extracellular TG2 in osteoarthritis are consequentially linked events.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Stage I - Developing and testing a PROMs tool for use across musculoskeletal care pathways._x000D_ Stage II - Piloting and testing of the M-PROM: a tool for use across musculoskeletal care pathways
Funder: Arthritis Research UK

Abstract: This project aims to improve clinical services for patients with musculoskeletal conditions such as back pain and osteoarthritis, by investigating how patients’ own feedback on progress can be used to evaluate the quality of services. The research plans describe a collaborative initiative between Keele and Oxford building on their previous research in this field to develop a multidimensional musculoskeletal patient reported outcome measure (M-PROM) that is meaningful to patients and clinicians with strong stakeholder buy-in (patients, professionals, service providers and commissioners). We will achieve this by developing an M-PROM tool, and then testing its acceptability, feasibility and applicability across the musculoskeletal community. This will include, consensus workshops with stakeholders from general practice, physiotherapy, rheumatology and orthopaedics, and face validity testing in small groups and individual cognitive interviews. Further research (beyond the remit of this strategic call) will then test the M-PROM’s measurement properties within a number of longitudinal patient cohorts from different musculoskeletal settings.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL
Title: 3D Technology Enhanced Patient Information (TEPI) for orthopaedic operations – Improving information and unmet needs of patients
Funder: Arthritis Research UK

Abstract: The prevalence of knee, hip and shoulder problems requiring orthopaedic surgery in the UK is now a considerable burden to the NHS. We have developed simulated information ‘applications’ for patients including three dimensional images and video of two common orthopaedic operations. We plan a qualitative project that will involve patients in further developing these applications and producing an online technology enhanced information resource for orthopaedic patients. Through focus groups and structured patient interviews, we will produce and assess an online resource containing downloadable three dimensional patient information. We will explore and assess unmet needs with our patients in order to produce a final product that will include patient video and audio recordings of their experiences. These will be made available on the TEPI site, the ARUK site and the Healthtalkonline site and will improve both public and professional understanding of what information orthopaedic patients undergoing surgery need and desire.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Shedding of endocytic receptor LRP1 promotes osteoarthritis by altering extracellular trafficking of metalloproteinases.
Funder: Arthritis Research UK

Abstract: Cartilage degradation in osteoarthritis (OA) is now well established to be the result of elevated proteinase activities, with the key enzymes being aggrecanases and collagenases. This application is based on our recent discovery that aggrecanases (ADAMTS-4 and ADAMTS-5) are rapidly endocytosed by chondrocytes in healthy cartilage via low-density lipoprotein receptor-related protein 1 (LRP1), but this process is impaired in OA cartilage due to increased shedding of LRP1, which results in increased extracellular activities of aggrecanases and collagenase 3 (MMP-13). This implies that aberrant LRP1 shedding leads to early OA lesions characterised by proteolytically-mediated degradation of the extracellular matrix. The aims of this project are: 1) to identify and characterise the LRP1 ‘sheddase’ in cartilage and investigate how shedding of LRP1 modulates cartilage matrix-degrading proteinase activities; 2) to delineate the critical role of LRP1 shedding in OA pathogenesis by using a mouse model of OA and by assessing changes in LRP1 levels in normal human articular cartilage and in early OA lesions. Accomplishment of these aims will reveal a novel pathogenic pathway of OA and specific targets towards the development of disease-modifying drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The role(s) ADAMTS4 and its splice variant ADAMTS4_v1 play in the pathogenesis of human osteoarthritis
Funder: Arthritis Research UK

Abstract: The major enzymes responsible for cartilage aggrecan catabolism in the pathogenesis of osteoarthritis (OA) are called the "aggrecanases"; i.e. ADAMTS4, ADAMTS5 (both found in cartilage) and a newly discovered splice variant called ADAMTS4_v1 that is only found in synovial tissue isolated from human OA patients. However, at present, researchers do not know which of these three 'aggrecases' are involved in the different stages of the onset & progression of OA pathology. We hypothesise that the synovium-derived ADAMTS4_v1 and cartilage-derived ADAMTS4 play pivital roles in cartilage aggrecan degradation particularly in the surface zones of cartilage in the initial stages of OA onset and cartilage destruction. Experiments to address this hypothesis will include; Aim-1: Development of ELISA-based assays to quantify the presence of ADAMTS4 & ADAMTS4_v1 in synovial fluids of stratified patient populations with different sources of degenerative joint disease; Aim-2: To use in vitro Transwell co-culture systems with human patient synovium and bovine articular cartilage explants to determine the mechanisms of ADAMTS4_v1 translocation from the OA synovium to the articular cartilage; & Aim-3: To use truncated isoforms of ADAMTS4 & ADAMTS4_v1 as allosteric inhibitors of "aggrecanase activity" in culture systems that mimic cartilage matrix degradation in degenerative joint diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Development of an outcome prediction tool for patients considering a total knee replacement – the Knee Outcome Prediction Study (KOPS)
Funder: Arthritis Research UK

Abstract: Knee osteoarthritis affects 10% of the UK population over 55 years. Knee replacement is a treatment that has a proven benefit and 79,516 total knee replacements were performed in England and Wales in 2011. However, approximately 17% of people are dissatisfied after surgery. As a consequence some commissioning groups have reduced access to this treatment._x000D_ _x000D_ Previous work examining the surgical technique or rehabilitation has not been able to account for the all of variation in outcome. Recent studies have suggested that patient factors, such as patient’s age or co-morbidities, have a very large effect on outcome._x000D_ _x000D_ This study’s goal is to develop a clinical tool that provides a personalised prediction of outcome based on patient factors. This should improve patient satisfaction, by more accurately aligning patient expectations with predicted outcome. This represents a form of personalised medicine, and is aligned with the research strategy of Arthritis Research UK’s Orthopaedic Surgery Clinical Studies Group, Arthritis Research UK’s strategy to improve access to stratified and personalised medicine for patients with knee osteoarthirits, and Arthritis Research UK’s Hip and Knee Arthroplasty Research agenda. _x000D_ _x000D_ The findings from this project will inform national policy making and regional service provision.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Increasing physical activity in older people with chronic musculoskeletal pain: A brief and simple intervention to promote walking
Funder: Arthritis Research UK

Abstract: The primary objective is to investigate whether a brief and simple behavioural intervention increases the time spent walking at 6 months in adults aged 65 years and over with chronic pain that impacts on their daily activities. However before conducting that study, this application is to fund intervention development work and to conduct a pilot RCT._x000D_ The primary objectives of the development work are to agree What should be delivered; How should it be delivered; and Who should deliver it?_x000D_ We will then conduct a pilot RCT to determine the feasibility of conducting the main trial. This study will address whether we can engage GP practices to participate and stay in the trial through follow-up; recruit, train and retain sufficient intervention deliverers; recruit and retain at least 1 in 3 eligible patients to the trial within the proposed timeframe; achieve sufficiently high response rates to follow-up questionnaires and other study materials; achieve sufficiently high follow-up rates; demonstrate intervention adherence rates; achieve delivery of the intervention in line with agreed intervention protocols; and demonstrate the feasibility of collecting primary outcome data using accelerometers.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL
Title: Working with hand osteoarthritis: Development of a musculoskeletal model for ergonomic assessment
Funder: Arthritis Research UK

Abstract: An estimated 2.7 million people in the UK suffer from a debilitating lack of manual dexterity. Hand osteoarthritis is a leading cause, with 21% of people over the age of 40 affected by arthritis in the thumb. As the population seeks to maintain an active lifestyle for longer, the activities they perform on a daily basis have greater implications for lasting joint health. Loading on the joints is known to play a role in the progression of osteoarthritis; however, without surgery joint loads cannot be measured directly. Therefore, the purpose of this work is to create a novel musculoskeletal model of the hand and wrist, building upon prior upper limb modelling to create a more complete picture of the loads we apply to our joints. Model outputs will be compared to clinical assessment tools and used to study the forces in the hand and wrist during everyday tasks in people with and without osteoarthritis. This will advance our understanding of the types of activities that carry the highest risk for damaging the joints and provide a quantitative measure of the biomechanical effects of current strategies to assist osteoarthritis patients and how these may be improved.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Epigenetic factors in fibromyalgia: an omics study
Funder: Arthritis Research UK

Abstract: Chronic widespread musculoskeletal pain (CWP) is a common condition, poorly understood and inadequately managed. Presenting with sleep disturbance it is labelled fibromyalgia. Fibromyalgia is known to have a genetic basis and a few candidate genes have been proposed. The first genome-wide association meta-analysis was recently performed but in keeping with many common complex traits, the proportion of heritability explained by these variants remains small. Epigenetic modification by, for example, methylation of DNA may provide the link between genetic variants and environmental influence in expression of common complex traits. There are many other biological steps between DNA code (genomics) and the end phenotype (fibromyalgia) including gene transcription, translation and post-translational modification. Such “omics” measures (transcriptomics, metabolomics, glycomics etc) reduce the “distance” between DNA and phenotype and improve the signal to noise ratio, allowing discovery of new associations and identification of pathways leading to pathology._x000D_ This project's aims are to:_x000D_ identify methylation differences in fibromyalgia explore other omics in relation to known genetic variants identify novel biomarkers of fibromyalgia This project uses existing data – genetic, epigenetic and ‘omic - available in TwinsUK to answer questions about the abnormalities present in fibromyalgia, and to identify biomarkers for CWP.


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