NIHRDataInsights/HRCSData huggingface dataset:
Title: Defining the molecular mechanisms involving microfibrils and ADAMTSL2 that lead to skeletal dysplasias
Funder: Versus Arthritis

Abstract: Acromelic dysplasias, including geleophysic dysplasia and Weill-Marchesani syndrome, are a newly described group of disorders caused by mutations affecting fibrillin-1, which is the major component of the 10-12 nm diameter extracellular microfibrils. In contrast to the tall stature and cardiovascular symptoms associated with Marfan syndrome, these disorders result in short stature, joint stiffness and skin thickening. Despite the opposing phenotypes, TGFß dysregulation is a feature of all these diseases. The acromelic dysplasias are also caused by mutations affecting ADAMTS and ADAMTSL proteins, suggesting an overlap of the function of these proteins and fibrillin-1. As part of our current Arthritis Research UK grant, we have investigated interactions of fibrillin-1 with ADAMTSL2, which is linked to geleophysic dysplasia. We also developed a novel assay to determine the effects of disease-causing mutations and the roles of individial fibrillin-1 domains in microfibril assembly, showing a major role for the fibrillin-1 C-terminal propeptide. We aim to build on these data to investigate ADAMTSL2 interactions involved in TGFß regulation, including interactions with LTBP-1, and further investigate the structure and interactions of the fibrillin-1 C-terminal propeptide. This will increase our understanding of a wider group of diseases, including scleroderma, and provide mechanistic insights into matrix regulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Enhancing Chondrogenesis via modulation of Sirt1 activity for cartilage repair
Funder: Versus Arthritis

Abstract: Based on published work this project will test the hypothesis that the protein deacetylase Sirt1 enhances chondrogenic differentiation from human Embryonic Stem Cell (hESCs), and drives cartilage matrix generation towards achieving a transplantable tissue. To test our hypothesis we will (1) Characterize SIRT1 expression and activity in transactivating COL2A1 expression. We will further examine SIRT1 regulation of Sox9 acetylation levels and its functional attributes by Chromatin immunoprecipitation (ChIP) for the COL2A1 enhancer. (2) Determine the impact of SIRT1 knock-down at different stages in chondrogenesis to pinpoint the stage at which expression and activity are critical for the process (3) Characterize genome-wide SIRT1 regulatory activity during chondrogenesis using ChIP-sequencing and custom microarrays for identified SIRT1 targets. (4) Determine the combined effect of growth factors and SIRT1 modulators on cartilage matrix production by hESC-chondrogenic cells and (5) Evaluate cartilage regeneration in-vivo in a rat focal defect model. Expectedly, these investigations will identify the role of a key regulatory target, driving cartilage matrix formation and identify novel strategies to repair cartilage in joint diseases such as OA. Improvements gained in the production of chondrogenic cells will be exploited in parallel work to develop new cell therapies for cartilage repair from clinical grade hESCs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Cordycepin as a lead compound for the treatment of osteoarthritis pain
Funder: Versus Arthritis

Abstract: Cordycepin (3’ deoxyadenosine) is a bioactive compound isolated from a popular traditional medicine. We have demonstrated that cordycepin inhibits inflammatory gene expression at a post-transcriptional step by inhibiting polyadenylation leading to inhibition of cytokine and chemokine mRNA expression. In addition, cytoplasmic polyadenylation plays a major role in synaptic plasticity and has recently been implicated in sensitisation of nociceptors. Indeed, cordycepin reduced pain behaviour in the monosodium iodoacetate (MIA) model of osteoarthritis in rats. We will evaluate the effect of cordycepin on pain behaviour in two surgical models of osteoarthritis pain: meniscal transection (MNX) in rats medial meniscal displacement (MMD) in mice. Tissues will be examined for changes in joint morphology, known biochemical markers of osteoarthritis and known biochemical markers of the action of cordycepin, using microscopy and RNA analysis. We will determine whether cordycepin is effective in other models of osteoarthritis and at which tissues, cells and mRNAs cordycepin treatment produces these effects, and the mechanisms of action specific to osteoarthritis. In addition, we will perform pharmacokinetics and biodistribution studies of cordycepin to determine which tissues accumulate it. These studies may ultimately lead to the design of novel medicines for osteoarthritis pain based on cordycepin as a lead compound.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Quantitative 3-dimensional assessment of multi-tissue pathology in knee osteoarthritis
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is increasingly common but current symptomatic therapy is not adequate. Structure modification has proven elusive despite increasing knowledge about OA pathology, largely because we have lacked the tools to holistically assess joint structure. Statistical shape models (SSMs) provide a tool for precise quantitative, whole-joint, 3D structural assessment of magnetic resonance images (MRIs). We have developed SSMs to measure cartilage and bone within the knee joint, with SSMs for menisci and synovitis in progress. We have used these SSMs to analyse MRIs, collected annually for 7 years, from the 4,796 participant Osteoarthritis Initiative (OAI) cohort of people with, or at risk of, knee OA. Using this data, together with clinical and patient-reported data, we wish to conduct a holistic analysis which integrates these individual SSMs to examine the joint as a whole. We will use sophisticated statistical modelling to explore the spatial and temporal inter-relationships that occur between the different tissues within the knee during OA symptomatic and structural progression. The outcomes from this programme will provide a step-change in our understanding of the mechanisms of OA progression, define pre-OA asymptomatic and symptomatic states, identify novel risk factors for progression and novel phenotypes for true phenotype-stratified interventions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Individualisation of biological therapies for Osteoarthritis – understanding and reducing failures
Funder: Versus Arthritis

Abstract: The pathology of failure in currently used biological treatments (cell therapies and microfracture) for cartilage repair or early osteoarthritis (OA) is poorly understood. We have used state-of-the-art quantitative proteomic techniques to identify novel predictors of success/failure in the synovial fluid of a small subset of our cell therapy patients. In addition, we have quantified several known biological indicators of OA progression in the synovial fluid and show there to be increased aggrecanase type 1 (ADAMTS-4) activity in failed patients. Further, we have shown that the function of cells implanted into patients’ joints may be directly and deleteriously affected by elevated ADAMTS-4 activity. This proposal aims to identify a reliable panel of biological predictors (examining both biochemical and cellular components of synovial fluid and blood) which can be used in the preoperative setting to optimise patient selection and therapy efficacy. We will not only investigate biological mechanisms of action for some of the novel predictors we identify but also use them to develop and target individual treatments for patients. The long term aim is to reduce the number of patients who progress to end-stage OA and require knee replacement by making earlier, less invasive treatments more effective.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: The Effect of Denosumab on Pain and Bone Marrow Lesions in Symptomatic Knee Osteoarthritis: A Randomised Double Blind Placebo Controlled Clinical Trial - DISKO
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) of the knee is a common disorder for which there are few effective therapies. There is increasing evidence, however, that bone active therapies, may reduce symptoms and have structure modifying effects. In a recent pilot study, for example, in patients with symptomatic knee OA, treatment with intravenous bisphosphonate was associated with reduced pain and bone marrow lesions (BMLs) on magnetic resonance imaging (MRI). Denosumab is a monoclonal antibody targeted at RANKL and a potent antiresorptive agent. The aim of this trial is to determine whether, in patients with symptomatic knee OA and BMLs on MRI, denosumab is associated with reduced knee pain and reduction in maximal area of BMLs. 166 men and women aged 50 years and over with symptomatic knee OA and BMLs on MRI will be randomised (1:1 ratio) to receive either a one-off administration of subcutaneous 60mg denosumab or matched placebo. Assessments will include questions about pain intensity and a gadolinium enhanced MRI scan at baseline and 6 months. The primary outcome measure will be change in maximal area of BMLs at 6 months, with change in knee pain using an 11 point (0-10) numerical scale of pain intensity as the main secondary outcome.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Fibrillin-1 in articular cartilage health and osteoarthritis development
Funder: Versus Arthritis

Abstract: Fibrillin-1 is a glycoprotein found in the pericellular matrix of articular cartilage (AC). My studies show its loss with osteoarthritis in a spontaneous (Str/ort) and a trauma-induced model of osteoarthritis, increased Fibrillin-1 mRNA in Str/ort mouse chondrocytes, and mutation in Fibrillin-1 leads to increased OA severity in Tight skin mice. The main roles of Fibrillin-1 were determined in other tissues will be assessed in my aims. Human and transgenic mouse models, with cartilage Fibrillin-1 deficiency and Fibrillin-1 mutation (Tight skin mouse), and in vivo and in vitro models of mechanical trauma, which I have pioneered, will be used. My first aim is to determine the mechanical role of Fibrillin-1 in AC and its contribution to post-traumatic OA development. My second aim is to define the role of Fibrillin-1 in chondrocytes mechanotransduction, in particular through interaction with integrin-ß1. My third aim is to describe the effects of Fibrillin-1 deficiency and degradation on growth factor signalling in AC, including TGFß and PDGF. This project will determine the role of Fibrillin-1 in AC and the effects of its loss to define whether fibrillin-1 and its downstream functions are viable targets for therapy against OA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: A randomised, double-blind, placebo-controlled two period crossover study to evaluate the efficacy of tofacitinib in relieving pain in patients with osteoarthritis of the knee - JAKPOT
Funder: Versus Arthritis

Abstract: Osteoarthritis is of massive and growing importance to the UK, its current treatmetns are limited in efficacy and have significant side effects limiting their use. Inflammation is very common in osteoarthritis and is associated with the presence and severity of pain. There is increasing evidence for the role of pro-inflammatory cytokines in the OA disease process. The JAK-STAT pathway is a major regulator of cytokine signalling and has been shown to be upregulated in OA. Tofacitinib is a JAK kinase inhibitor which has demonstrated good efficacy and safety in treating inflammation in rheumatoid arthritis. Given our increasing understanding of the role of JAK-STAT in OA pathogenesis, we believe that the time is right to conduct a pivotal clinical study to evaluate the potential efficacy of tofacitinib as an analgesic treatment for painful knee osteoarthritis. We propose an 8 week, first-in-disease, phase II, randomised, double-blind, placebo controlled two period crossover study to evaluate the safety and efficacy of tofacitinib against placebo in subjects with osteoarthritis pain of the knee. Positive analgesic benefits in this study have excellent potential to lead to large phase III trials and impact in a field with huge unmet needs in pain relief.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Targeting circadian clock mechanisms in articular cartilage towards therapies
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is the most prevalent joint disease (8 million sufferers in the UK), causing severe pain, deformity and a loss of mobility, with currently no cure. Age is a major risk factor. However, the reasons why OA susceptibility increases with age are poorly understood. My group has recently discovered a functional link between the disruption of the chondrocyte circadian clock and cartilage degeneration. Therefore, it is timely to explicitly demonstrate the mechanistic links between the chondrocyte clock and cartilage homeostasis/pathologies (such as OA). This new avenue of research holds strong potential to identify drugs (e.g. clock acting compounds) or novel therapeutic routes (e.g. an imposed circadian rhythm) for this debilitating disease, which affects most elderly people.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: ECM-sequestered GCP2: an unexpected chondrogenic factor
Funder: Versus Arthritis

Abstract: We recently reported that ELR+CXC chemokines bound to heparan sulphate proteoglycans in the chondrocyte pericellular matrix supply an autocrine/paracrine homeostatic signal that protects cartilage from degradation following induction of cartilage instability. Mechanistically, we discovered that CXCR2 activation in chondrocytes supports SOX9 expression in an AKT-dependent manner, protects chondrocytes from apoptosis and mice from instability-induced osteoarthritis (Sherwood et al. 2014).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Sulfation patterns of pericellular heparan sulfate regulate chondrocyte homeostasis: novel targets for OA therapy?
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) remains a disease with great social and economic impact world-wide due to the lack of available disease-modifying therapies. To make the step-change required, greater understanding of the cellular and molecular processes of OA pathogenesis is required. In a pilot study, we identified a novel group of genes that are dysregulated in OA chondrocytes and that we propose disturbs cartilage homeostasis and promotes OA development. These genes determine sulfation of heparan sulfate (HS) proteoglycans in the pericellular environment of cartilage, and hence regulate localisation and bioactivity of HS-binding growth factors and inhibitors of the metalloproteinases that degrade cartilage tissue. We will establish what specific changes in HS sulfation patterns occur during development of OA, and compare these with changes to sulfation patterns that occur with ageing. This will reveal which HS sulfation patterns and HS biosynthesis and modifying enzymes are associated with normal ageing, and which correlate with pathological cartilage damage. This study will establish a novel molecular mechanism of OA pathogenesis and identify new targets for the development of OA therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Development of a Personalized Health Forecasting Tool for Patients Undergoing Hip or Knee Replacement
Funder: Versus Arthritis

Abstract: Shared-decision making between a patient and their doctor is fundamental to good clinical practice, and improves patient knowledge about medical treatments and their associated risks and benefits. The risk of death and revision surgery after joint replacement varies substantially with individual patient characteristics, procedure, and prosthesis selection. In preference-sensitive decisions, such as joint replacement, evidence-base decision making empowers the patient arrive at an informed, preference-based choice among many treatment alternatives. The National Joint Registry for England, Wales and Northern Ireland (NJR) is the world’s largest arthroplasty register, containing records of over 1.6 million patient episodes. We will use the NJR dataset to develop and validate a decision aid for patients with hip or knee arthritis who are considering surgery. We will apply our expertise in population level risk modelling to build personalised decision aids using advanced linear and non-linear regression models within a general Kaplan-Meier framework. The tool will provide personalized competitive-risk based outcomes predictions for surgical mortality and prosthesis revision over 10 years, given a range of fixed and modifiable risk factors. The development team includes members with expertise in joint registry outcomes analysis, predictive modelling techniques, decision aid development (FRAX), and software engineering to web-enable the completed tool.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL
Title: Understanding the mechanism and regulation of TSG-6’s protective activity in OA cartilage
Funder: Versus Arthritis

Abstract: There is increasing evidence that TSG-6’s biological role is to protect tissues from the damaging effects of inflammation, i.e. forming part of an intrinsic protective pathway. During our ARUK programme grant we have discovered that TSG-6 suppresses cytokine-induced expression of cartilage-degrading enzymes by human chondrocytes, where a recombinant fragment of TSG-6 (Link_TSG6) is more potent than the full-length protein. Importantly, we have shown that TSG-6 reduces proteoglycan loss in vitro and that Link_TSG6 has therapeutic potential to treat osteoarthritis, limiting cartilage breakdown (and reducing pain) in a rat model of OA. Our data indicate that Link_TSG6 may mimic a naturally occurring proteolytic fragment, such that processing of TSG-6 could provide positive feedback to stimulate further TSG-6 expression by chondrocytes. The aim of this project is to determine the mechanism by which TSG-6 supresses cytokine function and how it is regulated in cartilage. In particular, we will determine: i) how TSG-6 affects intracellular signalling pathways in chondrocytes, ii) if its chondroprotective activity is mediated through the modulation of cell-matrix interactions and iii) whether the processing/turnover of TSG-6 regulates its functions in human OA cartilage. These mechanistic insights will greatly facilitate our translation to the clinic of a TSG-6-based biological for OA.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Using CRISPR/Cas9 genome editing to identify therapeutic targets of microRNAs
Funder: Versus Arthritis

Abstract: MicroRNAs show great therapeutic promise and clinical trials are underway to treat a variety of human diseases. However, since a single microRNA can (and does) target multiple genes, for both efficacy and safety concerns there is a clear need to identify and selectively affect only the relevant (beneficial) target sites. No current approaches can do this and we will address this unmet need through the use of state-of-the-art genome editing technologies. To this end we have developed a very potent strategy using CRISPR/Cas9 mediated homology-directed repair for the assessment of microRNA response element (MRE) activity in human cells. In the current study such an approach will be applied to human chondrocytes to enable identification of endogenously active microRNA binding sites in phenotypically important genes. We believe these MREs, rather than the microRNAs themselves, to be the most appropriate targets for future clinical trials.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Elucidating the role of vascular endothelial growth factor in regulating adult bone health, strength and repair
Funder: Versus Arthritis

Abstract: Bone is renewed throughout life and relies upon a constant blood supply providing it with oxygen and nutrients. Our research indicates osteoblasts (OBs) are a source of angiogenic factors such as vascular endothelial growth factor (VEGF). Recently, we found that conditioned media from human osteoporotic bone explants contained low VEGF and induced endothelial cell (EC) apoptosis. We hypothesise that a reduction in the vasculature during osteoporosis is a consequence of deficient VEGF production by OBs promoting vascular EC apoptosis and contributing to reduced bone strength, increased fracture risk and compromised repair. The studentship will investigate this in detail using a mature osteoblast specific VEGF knock out model and i) study in vitro the effects of VEGF loss on OB and EC behaviour ii) examine the in vivo adult bone phenotype of this knock out by computed tomography and measurements of bone strength and iii) Utilise a unique ex vivo fracture healing model to examine how bone repair is altered in the absence of osteoblast VEGF. Reversal effects will be explored by adding VEGF producing skeletal stem cells to a fracture defect. Results could have direct translational impact in the areas of fracture repair and regenerative medicine specific to ageing bone.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The clinical effectiveness and efficacy of splinting for thumb base osteoarthritis: a randomised controlled trial - OTTER II
Funder: Versus Arthritis

Abstract: The economic burden of osteoarthritis (OA) is high. By 2020 OA is estimated to be the fourth leading cause of disability. At least 4.4 million people have hand OA in the UK. Symptomatic thumb base (carpometacarpal) OA affects 20% of the population over 55 years, causing more pain, work disability, reduced quality of life and function than OA elsewhere in the hand. International experts recommend splinting for hand OA but there is limited evidence from robust trials to support this. The potential effects of placebo interventions in osteoarthritis are acknowledged, but few studies investigate this impact. A multicentre, three arm, randomised controlled trial will determine the effectiveness and efficacy of verum thumb splints when delivered with a self-management intervention for people with symptomatic thumb base OA. Occupational therapy and physiotherapy centres in England will recruit 294 participants aged 30 years and over with clinical thumb base OA. The primary outcome is the AUSCAN hand pain scale. The study end point is 8 weeks. Outcomes will be collected at baseline; 4 weeks; 8 weeks; and 12 weeks. Findings will improve the management of thumb base OA and add to understanding contextual aspects of rehabilitation and self-management strategies for OA.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL