NIHRDataInsights/HRCSData huggingface dataset:
Title: Does the vasodilatory action of PTH help account for its osteogenic effects?
Funder: Arthritis Research UK

Abstract: Parathyroid hormone (PTH), the only currently available treatment for increasing bone mass, has long been known to be a potent vasodilator, acting directly on blood vessels. Many lines of evidence indicate that new bone formation is dependent on a good blood supply. Our preliminary data show that PTH injection rapidly causes increased blood flow to bone in mice. We wish to investigate the hypothesis that this some of the osteogenic action of PTH could be due to this effect. The main research questions are: 1) to measure the effects of PTH on the flow of blood to mouse bones and to determine whether the acute vasodilatory action of a single dose of PTH is abolished when PTH is administered continuously; 2) to establish whether longer term intermittent / continuous PTH also affects the formation or size of blood vessels in bone; 3) to determine whether the anabolic action of longer term intermittent PTH is abrogated when PTH is co-administered with a vasoconstrictor. Blood flow measurements will be correlated with microCT and histomorphometric analyses of bones. This study will shed light on the mode of action of PTH and could point the way to new anabolic therapies for bone.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: The biological functions of chondroitin/dermatan sulphate sulphation motifs in musculoskeletal tissue growth & development
Funder: Arthritis Research UK

Abstract: The overall objective of this study is to better understand the biological mechanisms underlying the specific and dynamic/spacio-temporal expression of CS/DS sulphation motifs on cell surface and matrix proteoglycans in order to further understand the role they play in tissue & organ growth and development. The Aims to achieve this objective are;_x000D_ _x000D_ Aim 1: To use purified mAbs recognising native CS/DS sulphation motifs as “blocking antibodies” to analyse how this perturbs the differentiation and proliferation of bovine bone mesenchymal stem cells (MSCs) to chondrogenic lineages._x000D_ _x000D_ Aim 2: To produce siRNA probes for specific glycosyl- & sulpho-transferases that are involved in CS/DS biosynthesis and ascertain their effects on the proliferation and differentiation of bovine bone MSCs to chondrogenic lineages._x000D_ _x000D_ Aim 3: To use the in ovo chicken embryogenesis model to determine the effects of agents that perturb CS/DS biosynthesis, sulphate substitution & biological functions on cell and matrix proteoglycans (i.e. b-xylosides, siRNA probes & ‘blocking’ antibodies) have on musculoskeletal tissue development and growth.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Can We Use Clinical Foot and Ankle Assessment to Improve the Prediction of Patient Reported Outcomes in Total Knee Arthroplasty?
Funder: Arthritis Research UK

Abstract: Objectives: To determine whether clinical foot and ankle measures are useful in predicting patient reported outcomes following Total Knee Replacement (TKR). An informed set of clinical foot and ankle assessments will be applied to a large cohort and evaluated against current measures of outcomes for knee arthroplasty._x000D_ _x000D_ Design: A prospective cohort study of clinical foot and ankle assessments in patients’ pre and post TKR. We will perform a baseline, 6 week and 12 month post-op data collection on a cohort of patients. An established Clinical Outcomes in Arthroplasty Study (COASt) cohort will be utilised. Additionally a comparative study of clinical and technical foot and ankle assessment will be carried out on a sub-group of participants._x000D_ _x000D_ Expected Outcomes: 1) The identification of a core set of clinical musculoskeletal foot and ankle assessments. 2) The determination of the contribution foot and ankle assessments provide to the prediction of patient outcomes following TKR. _x000D_ _x000D_ Anticipated benefits: Data collected will help us to identify if foot and ankle status contributes to the prediciton of outcomes for knee replacement. Findings may inform the use of foot and ankle assessment within current TKR care pathways and may potentially aid in enhancing the successful outcomes of TKR.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Prognostic indicators of successful rehabilitation outcome in patients with subacromial impingement / rotator cuff tendinopathy
Funder: Arthritis Research UK

Abstract: Shoulder pain is highly prevalent in the general population and a substantial cause of functional and work-related disability for the individual. Approximately one-fifth of all disability payments for musculoskeletal disorders are for patients with shoulder disorders._x000D_ _x000D_ Subacromial impingement and rotator cuff tendinopathy are the most common types of shoulder pain and are frequently managed conservatively. Reported levels of successful rehabilitation vary considerably. Consequently there is a need for research to inform targeted patient management and the optimal use of finite rehabilitation resources._x000D_ _x000D_ The proposed study will provide a foundation stage in a body of prognostic research relating to the conservative management of patients with subacromial impingement / rotator cuff tendinopathy. Using a longitudinal cohort design, relevant rehabilitation-specific and patient-specific characteristics of such patients will be collected._x000D_ _x000D_ Analysis will determine clinically important subgroups and the magnitude of prognostic effects attributable to them, informing follow-on research where pre-specified hypotheses about sub-grouping effects will be prospectively tested. Via patient triaging, resources will be prioritised and NHS costs reduced. Patients will benefit from improvements in function and quality of life, whilst industry and society will benefit from a reduction in shoulder-pain related work and social burdens.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.4 POPULATION SCREENING
Health categories: MUSCULOSKELETAL
Title: The effect of the “degenerate intervertebral disc niche” on mesenchymal stem cell differentiation and function: Implications for intervertebral disc regeneration
Funder: Arthritis Research UK

Abstract: Low back pain affects a large proportion of the UK population and is associated with intervertebral disc (IVD) degeneration. Current treatments are inadequate, leaving a need for novel therapies aimed at alleviating low back pain through IVD regeneration. Mesenchymal stem cells (MSCs) have the potential to be used for repair of the degenerate IVD, however the effect of the human degenerate “niche” on the success of this proposed therapy remains unknown. If the unfavourable conditions within the degenerate IVD “niche” prove detrimental for MSC differentiation in vivo, then pre-differentiation of cells prior to implantation could be necessary. The purpose of the proposed study is to, i) identify the most suitable source of MSCs (adipose or bone marrow-derived) for IVD regeneration under conditions mimicking that of the degenerate “niche”, ii) determine whether a hydrogel cell scaffold improves the success of implantation, and iii) ascertain whether pre-differentiation is a prerequisite for MSC -dependent IVD regeneration. The aforementioned will be achieved through a combination of in vitro and ex vivo culture experiments (including use of an accurate model of IVD degeneration), which will enable the progression of a novel stem cell therapy for regeneration of the IVD and help inform clinical practice.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: CIMA: The Centre for Integrated Research into Musculoskeletal Ageing
Funder: Arthritis Research UK

Abstract: The Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Newcastle and Sheffield, which aims to understand why our bones, joints and muscles function less well as we age and why older people develop conditions such as arthritis, osteoporosis and muscle weakness. The centre will also investigate new ways of preventing and treating the deterioration of the musculoskeletal tissues that occur as we age to help preserve mobility and independence in older people.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Centre for Musculoskeletal Ageing Research
Funder: Arthritis Research UK

Abstract: This Centre will integrate the work of world class researchers, clinicians and health professionals at the Universities of Birmingham and Nottingham to focus upon understanding how and why we lose muscle, bone and cartilage as we age, and the role played by factors such as inflammation, metabolism, altered hormones and obesity in this process. Researchers hope to detect the key factors which drive ageing of the cells and tissues that make up the musculoskeletal system and identify new drugs and lifestyle changes which will reduce age related decline and keep individuals healthy and active for longer.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Targeted Intervention for Patellofemoral Pain Syndrome (TIPPS)
Funder: Arthritis Research UK

Abstract: This study is part of a programme of work investigating the role of targeted intervention in patellofemoral pain syndrome (PFPS). Recent literature and the First International PFPS Research Retreat (Davis & Powers 2010) have strongly promoted the idea of sub-grouping PFPS patients and delivering targeted treatment; it is believed that this may be more beneficial and/or less costly than the current therapeutic approaches. Despite numerous recomendations from the worlds experts as yet this premise has not been investigated. We have recently completed preliminary work (Phase 1) of a review of the literature which provides evidence for a number of PFPS sub-groups which could be identified by clinical assessment tests used in routine practice by phyisiotherapists and for which there are credible treatment interventions. However we don't know how often patients fall into these sub-groups and whether these sub-groups are mutually exclusive._x000D_ _x000D_ The key goals of this feasibility study are to assess:_x000D_ _x000D_ _x000D_ the relative frequency with which patients fall into each of the sub-groups_x000D_ whether the sub-groups are mutually exclusive or not


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: Functional analysis of the osteoarthritis susceptibility locus located downstream of the parathyroid hormone-related protein gene PTHLH
Funder: Arthritis Research UK

Abstract: The arcOGEN study, funded by Arthritis Research UK, has proved to be particularly effective at identifying robust osteoarthritis (OA) susceptibility loci by genome-wide association scan analysis. Based on a large discovery sample size of over 7,400 cases, combined with a focus on severe end-stage disease, arcOGEN has so far discovered five genome-wide significant signals. A signal at chromosome 12p11.22 is particularly interesting, with a p-value 1.48x10-8 at SNP rs10492367 in patients with hip OA. This SNP is located downstream of PTHLH, which codes for parathyroid hormone-related protein (PTHrP). This protein has a critical role in endochondral bone development by regulating chondrocyte proliferation and hypertrophic differentiation._x000D_ PTHLH is a striking candidate for the 12p11.22 OA association signal. Since the signal is not located within the gene itself, our hypothesis is that the association is accounted for by cis-acting regulatory variant/s that modulate the expression of PTHLH. In this application, the student will use a number of molecular and cell biology techniques to identify and characterize such variants for their potential role in regulating PTHLH expression and for their role in contributing to the association signal.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Walking on water. Mechanical and material properties of cartilage subjected to physiological or pathological loading
Funder: Arthritis Research UK

Abstract: The most common models of cartilage consider it as a porous solid, despite it comprising 80% water, and are limited in their ability to predict mechanical properties from measurements of composition and structure. The rapid growth of tissue engineering approaches to cartilage repair require a more fundamental understanding of material and mechanical properties in order to grow tissue with the required strength and toughness. This study will model new paradigms of cartilage as a structured fluid, more like a gel, to try to resolve the existing paradoxes in measurements, and enable measured material properties to be used as predictors of mechanical behaviour rather than variables in a curve fitting exercise. Measurements will be made of the mechanical properties of human and bovine articular cartilage over a wide range of loading rates covering the physiological and pathological range. High-speed imaging will record dimensional changes. Polarized light and Raman microscopy will measure collagen organization and composition respectively, supported by biochemical assessments. Multiphysics modelling, including theories of fibre composites, molecular modelling, fluid dynamics and electrostatics, will be used to develop models relating material properties to mechanical behaviour.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Investigating how chondroitin sulphation state affects local cartilage matrix signalling in vivo
Funder: Arthritis Research UK

Abstract: Osteoarthritis (OA) is a painful degenerative joint disorder, affecting millions of people worldwide. It is characterised by loss of joint cartilage, subchondral bone thickening and formation of bony spurs known as osteophytes. To understand the mechanisms underlying OA progression we must understand how the correct balance between cartilage and bone is established and maintained in the joint._x000D_ We have previously identified a zebrafish mutant with a progressive cartilage and joint phenotype resembling human OA. We have mapped the causative gene, chst11, a sulphotransferase that generates chondroitin-4-sulphate and dermatan sulphate; important constituents of cartilage matrix. This gene has also recently been named as a candidate gene linked to human OA. In chst11 mutants we see a range of effects on chondrocytes and osteoblasts which we hypothesise are due to changes in local signalling caused by changing cartilage matrix sulphation. Therefore, this project aims to establish how the sulphation state of the cartilage matrix, in particular the composition of chondroitin and dermatan sulphate affects growth factor signalling in vivo, and how this in turn affects the cells of the skeletal system in development and in progression of osteoarthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Targetting MyD88-dependent pathways to treat osteoarthritis
Funder: Arthritis Research UK

Abstract: Studying pathogenesis of osteoarthritis (OA) is challenging, and progress in recent years has come largely from animal models. Such studies have identified the prinical enzymes involved in cartilage breakdown, but the pathway/s that drives protease expression in vivo remains unknown. We investigated the role of MyD88, an adaptor protein involved in signalling through the IL1 receptor and TLR families. MyD88 knockout mice were strongly protected from surgically-induced OA and showed a global reduction in early inflammatory gene expression in the joint. Protection did not appear to involve either IL1 receptor or TLR2/4 activation as knockout animals for these receptors were not protected from OA. Several other other up-stream ligands/receptors that utilise MyD88 have been screened (results awaited). We will use available inhibitors (to MyD88 or upstream activators) to determine how to prevent OA in mice and whether these same pathways are required for progression as well as initiation of disease. Finally, we have established a new cohort of acute knee injury patients which will be followed over 5 years with serial serum and radiographic measurements. We will confirm whether MyD88-dependent pathways are activated early following human joint injury, and whether MyD88-dependent genes represent potential biomarkers for disease outcome.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Epigenetic analysis of osteoarthritis susceptibility loci
Funder: Arthritis Research UK

Abstract: This grant will support the creation of a new centre in Glasgow in which we will perform studies that aim to:1.Understand why arthritis occurs, and especially why it starts and why it does not get better on its own.2. Explore the ability of new medicines to improve different forms of arthritis 3. Understand better how current medicines work in people with arthritis so that we can perhaps improve on these in the future. 4. Find new approaches that can predict which medicine will work best for an individual person.5. Form part of a network with similar centres throughout the United Kingdom with a view to providing a concerted effort to perform the best studies possible


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Validating ADAMTS-4/5 as targets for therapy in a naturally occuring mouse model of osteoarthritis
Funder: Arthritis Research UK

Abstract: A key feature common to all forms of osteoarthritis is the degradation of articular cartilage. Various enzymes can contribute to this degradation and animal OA models are crucial in identifying those which are vital. The most commonly used model relies upon surgically-induced joint destabilisation and this has pinpointed ADAMTS-4/5 mediated cartilage degradation as key. It remains possible that alternative pathways of cartilage degradation are utilised in other models. This proposal will test the hypothesis: that the mechanism underlying naturally-occurring OA differs from surgically induced OA and therefore is unresponsive to selective targeting of ADAMTS-4/5. This will be achieved by: i) defining whether overexpression of [-1Ala]TIMP-3, a novel molecularly-modified protease inhibitor that selectively blocks ADAMTS-4/5 but not metalloproteinase activity, protects against load-induced development of OA-like lesions; ii) establishing if transgenic [-1Ala]TIMP-3 overexpression protects Str/ort mice against their natural susceptibility to OA and, iii) determining whether the [-1Ala]TIMP-3 transgene preferentially protects against mechanically-induced OA-like lesions in the loaded joints of Str/ort mice, but fails to modify spontaneous OA development occurring at distinct locations within the same joint. These studies will define if ADAMTS-4/5 are central to naturally occuring OA models and thus represent realistic targets for blockade in human disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Role of mutations in Sequestosome-1 isoforms in Paget’s disease of bone
Funder: Arthritis Research UK

Abstract: Paget's disease of bone (PDB) is characterised by focal lesions of increased bone turnover, driven by overactive osteoclasts. The best available treatments for PDB reduce osteoclast activity but do not improve pain or quality of life among sufferers. Mutations affecting Sequestosome-1 (SQSTM1/p62) ubiquitin-associated domain have been identified in individuals with PDB, which impair binding to ubiquitinated proteins targeted for degradation. We have identified a second, shorter isoform of SQSTM1 that is expressed in osteoclasts and other cell types, which is also mutated in PDB; and have found that the two SQSTM1 isoforms display different cellular expression profiles. The aim of this study is to examine the effect of PDB-causing mutations in both isoforms of SQSTM1 and determine whether mutations affect both isoforms similarly. Using model cell systems, we will (1) determine whether functional interaction between the two isoforms is impaired by mutations; (2) examine how the expression of the two isoforms differs between cell types; and (3) see whether osteoclast activity is similarly over-activated by mutations in both isoforms This work will improve understanding of the mechanisms underlying osteoclast over-activity in PDB, and help determine whether novel treatments for PDB should specifically target one or both isoforms of SQSTM1.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Understanding the Ontogeny of Mesenchymal Stem Cells in the Joint to Develop Tools to Study Osteoarthritis
Funder: Arthritis Research UK

Abstract: We recently identified functional mesenchymal stem cells (MSCs) in adult joint synovium in vivo. MSCs are thought to maintain joint tissues throughout life, representing an unprecedented therapeutic target to treat/prevent osteoarthritis. An increased understanding of their biology and improved tools to study them are required. We will test the hypothesis that such MSCs derive from the embryonic early-limb-bud mesenchyme and joint interzone. To track cells from these anatomical locations into adulthood, we will cross Prx1-Cre mice and Gdf5-Cre mice with Rosa26-LacZ mice, to identify cell-progeny from limb-bud-mesenchyme and joint-interzone cells, respectively. In the resulting Prx1-Cre/LacZ mice and Gdf5-Cre/LacZ mice, we will combine our established double-nucleoside-analogue labelling scheme with our validated joint-surface injury model to identify functional MSCs in the knee joint and will investigate co-detection of nucleosides and MSC markers with β-galactosidase. We will characterise the identified cells with combinations of MSC markers to determine which specific MSC subsets in synovium descend from the early-limb-bud-mesenchyme and/or joint-interzone cells. While addressing the developmental origins of MSCs in the adult joint, this study will also validate transgenic platforms that will enable conditional inactivation/overexpression of target genes in endogenous MSCs. This will revolutionise the way we study the role of MSCs in osteoarthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL