NIHRDataInsights/HRCSData huggingface dataset:
Title: How do circadian clocks in chondrocytes contribute to cartilage function in health and disease
Funder: Medical Research Council

Abstract: Circadian clocks drive ~24 hour rhythms in nearly all aspects of mammalian physiology and behaviour. Changes of circadian rhythms during ageing are now thought to underpin many of the age-associated pathologies. Our preliminary data demonstrates cell autonomous circadian clocks in the mouse cartilage tissue and human chondrocytes. Importantly, our cartilage circadian transcriptome profiling data strongly implicate circadian clocks as regulators of key genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in osteoarthritis (OA) pathogenesis. In this proposal, we will combine a novel transgenic mouse model with chondrocyte-specific ablation of circadian clock, with an experimental mouse OA model and with supporting human chondrocyte experiments to address the following key questions: 1) Which rhythmic genes in cartilage rely on the local chondrocyte clock to maintain their circadian pattern of expression? 2) Can we target cartilage circadian clock proteins as a novel approach to alter chondrocyte gene expression? 3) Do alterations in specific components of the clock mechanism cause early onset OA, or leave mice more susceptible to surgical injury-induced OA? These studies may identify novel strategies that target clock components or circadian rhythm to restore cartilage tissue homeostasis and prevent/delay arthritic disease onset. Such knowledge may also improve current treatments for joint diseases, for instance, by timing drug delivery to increase efficacy and reduce toxicity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Describing habitual levels of physical activity (PA) in older people in terms of impact loads and how this relates to bone and other systems
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We will use a combination of data previously or currently being collected in NSHD and HCS, future data collections funded separately, and data funded via this project comprising (i) accelerometers offered to all participants including a further cohort of Master Athletes, and (ii) and a bone study performed in a subgroup of NSHD and Master Athletes. Objective 1. Describe habitual PA according to level of impact load in older people The GCDC X16-1c tri-axial accelerometer will be posted out to participants, worn for 7 days, and number of counts derived within 0.3-0.9g (low eg normal walking), 1-1.5g (medium eg brisk walking), 1.6-2g (high eg aerobics class activities), >2g (very high eg jogging). Objective 2. Associations between impact loads and bone in older people Linear regression (adjusted for confounders - see objective 3) will be used to analyse counts within different impact bands in relation to: DXA and tibial pQCT as measured in the bone study; DXA, tibial pQCT and HRpQCT currently being measured in a subgroup of HCS; DXA obtained in the same HCS subgroup 12 months after accelerometry. Additionally, impact data will be extrapolated from previous from Actiheart data, and analysed in relation to hip BMD. Objective 3: Determinants of exposure to different impact loads Exposure to different impacts will be related to information about social, economic and psychological influences on PA from a questionnaire sent out with accelerometers, and information on physical performance and other health related factors obtained from face to face assessments. Objective 4: Associations between impacts and other systems in older people Exposure to different impacts will be related to variables relating to fat, muscle, cardiovascular, respiratory, and cognition. Objective 5: Acceptability, barriers and facilitators of activities of different impacts 30 individuals will be purposively selected from the bone study sample and interviewed face to face.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The consequences of motor unit remodelling for motor control: an important factor in the loss of mobility with old age.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: More than half the motor units in skeletal muscle can be lost by the age of around 75 yrs, but the surviving, predominantly slow, motor units are significantly enlarged. Our interdisciplinary approach will combine clinical and basic sciences to adDr.ess three main objectives: 1) Assess the extent of motor unit remodelling in the major locomotor muscles of older men; 2) Determine the extent to which motor unit remodelling is associated with difficulty completing daily tasks that are of critical importance for mobility and an independent lifestyle; and 3) Determine whether life-long physical activity modifies either the process of motor unit remodelling or leads to adaptations of neural control that compensate for the motor unit changes. Frail and healthy older men (n = 100) as well as older dancers and Masters Athletes competing in power and endurance events (n = 30) together with appropriate young controls (n = 80) will be recruited mainly from the large database of participants from our previous European Union-funded studies into ageing. Volunteers will be screened and undergo clinical assessments. Surface and intramuscular electromyography will be used to estimate motor unit size and number in large locomotor muscles. There will be comprehensive assessments of body composition and muscle size using DEXA and magnetic resonance imaging and detailed balance, walking and chair rising tasks. Statistical analysis will examine the motor unit size and number in association with balance and mobility and the extent to which different types of exercise can either preserve the motor units or maintain precise motor control. This work will be the most comprehensive assessment of motor unit remodelling during ageing to date. It will focus attention onto the motor neurons and motor units and open up new avenues of future research and lifestyle interventions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MUSCULOSKELETAL
Title: Acoustic Emission as a non-invasive biomarker for quantitative dynamic assessment of knee joint repair in clinical trials and stratified medicine
Funder: Medical Research Council

Abstract: We are the first to investigate high-frequency acoustic emission (AE) as a non-invasive, quantitative biomarker of the integrity of interactions between knee joint components during weight bearing movement (1-4). Our portable system uses wide-band AE sensors to detect sound waves with frequencies up to 200 kHz emitted from knees during sit-stand-sit movement. Similar principles are utilised in non-destructive testing and condition monitoring of engineering structures for early detection of damage and material defects. We are investigating various AE applications in clinical practice and research, and are progressing this work towards prototype development (see Project Plan). In this study we shall undertake technical validation of AE as a biomarker for enhancing the ability of clinical trials to provide relevant, robust evaluation of the growing array of new interventions aimed at improving or reducing deterioration in joint condition in knee OA. This study will enable us to investigate AE's utility to provide definition of patient subgroups for inclusion in clinical trials, and to inform stratified medicine approaches for optimising the use of such treatments in clinical practice. AE sensors are piezoelectric transducers which are attached to knee surfaces, using defined anatomical landmarks, to record short bursts of acoustic energy generated by stress upon, and friction between, joint components during weight-bearing movement. An electrogoniometer is attached to enable each acquired AE waveform to be linked to knee angle. A range of signal processing, analysis and visualisation methods has been developed based on AE waveform features in both time and frequency domains, AE statistics in different joint movement phases, and AE classification by principal component analysis. Our published results demonstrate that AE can distinguish not only between healthy and osteoarthritic knees, but also between knees in different age groups and differences in joint condition


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Biomaterials for Joint Soft Tissue Repair - Improving Health in Older Age
Funder: Medical Research Council

Abstract: Osteoarthritis is a currently incurable condition and a leading cause of functional disability and loss of independence in older adults globally, causing significant economic impact (1-2% GDP). This project proposes a novel cell-conducting osteochondral implant for the treatment of osteoarthritis and traumatic lesions of articular cartilage, which have a similar prevalence in Chinese and Caucasian populations. The implant is a polyvinyl alcohol-based hydrogel nanocomposite, which exhibits compositional/structural regions that mimic the appropriate biomechanical properties of the different regions of native tissue (i.e. subchondral bone, mineralised cartilage and cartilage) and support regeneration of cartilage tissue in situ. This implant should extend the pain-free function of osteoarthritic joints, thereby enhancing patient quality of life and mobility while reducing patient demands on health and social support services. In addition, the need for total joint replacement, with its potential problems of prosthesis loosening and limited lifespan, would be delayed. This collaboration brings together the requisite multidisciplinary and complementary strands of research, and essential scientific expertise, from the partner institutions into a world class team to conduct the project. The proposal builds on links made through the existing RCUK Science Bridges China programme and will receive additional support through the RCUK Global Exchanges programme.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Early life influences on skeletal growth - effects of vitamin D and mechanical loading
Funder: Medical Research Council

Abstract: 2 breeding female C57BI6 mice will be fed a Vitamin D deficient diet and housed in UVB-free lighting or a matched diet with Vitamin D3 and standard UVB lighting from age 4 weeks, and mated at age 10 weeks, continuing that diet throughout gestation. After weaning at 21 days 96 pups will be fed on either a Vitamin D deficient (under UVB-free light; dam=D replete/deficient; n=24/group) or replete diet (dam=D replete/deficient; n=24/group) until testing at age 10 or 20 weeks. Tibial loading will be performed under isoflurane anaesthesia by intermittent cyclical loading, i.e. 40 cycles daily of axial compression of the tibia 6 times over 2 weeks (weeks 8-10 or 18-20; n=12/group). Peak load magnitudes will achieve peak compressive strains on the tibial surface of 1200 microstrain (submaximal) and 600 microstrain (sub-threshold). Each group will go for microCT/histology (n=6) or indentation (n=6). Tibiae will be fixed in formalin, decalcified in EDTA and embedded in paraffin wax. Sections will be stained with either haematoxylin and eosin (H&E) or tartrate-resitant acid phosphatase (TRAP) to identify osteocytes. Immunohistochemistry will be performed using relevant primary mono/polyclonal antibodies by light microscopy using an ABC/DAB kit. MicroCT: Bone structure will be analysed using a microCT scanner (Skyscan). After image reconstruction and analysis a 3D micro finite element model of the tibia will be derived. Bone material properties will be estimated from microCT-equivalent bone density and fabric measurements. Boundary conditions will be defined by loading and strain and stress distributions calculated. Microindentation properties of mouse bones will be measured ex vivo using a BioDent Hfc Reference Point Indenter. Bones will be tested at 5 locations along the shaft; reference force of 270-310N, testing protocol of 2N at 2Hz over 5 cycles. Calculation of indentation distances and elastic properties will be provided through built-in BioDent software.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Biomechanical characterisation of joints in osteoarthritis mutant zebrafish; studying interactions between genotype and biomechanics in osteoarthritis
Funder: Medical Research Council

Abstract: Recently, several genes conferring increased risk of osteoarthritis (OA) have been identified. Currently, the mechanisms by which OA genes exert their effects on joints are largely unknown. We have data demonstrating that one of these genes, Chst11, alters gross joint morphology and chondrocyte maturation in developing zebrafish. Changes to joint shape are progressive; leading to joint failure at day 14. We will test the relationship between genotype and biomechanics in joint development. Using confocal microscopy to visualise muscle, cartilage and bone, we will develop finite element (FE) models of the jaw cartilages, their joints and associated muscles in wild type (wt) and chst11 mutant fish. FE-models are commonly used to deduce functional strain in engineering contexts and have increasing utility in animal biology. Our FE-models will map the positions of strain within the joint. We will then use the FE-models twinned with in vivo experiments to establish the extent and mechanism by which chondrocytes (in wild type and mutants) are influenced by mechanical strain. We predict that differing joint morphologies will generate different strain responses between wt and mutant fish. We will assay chondrocyte proliferation, maturation and matrix secretion in wt, active and anaesthetised mutants. We predict that changes to mechanical environment (e.g. decreased strain in anesthetised mutants) will lead to changes to local growth factor signalling. In vitro data implicates Chst11 in Wnt signalling; we also have preliminary data that Wnt signalling in the joint is suppressed following jaw immobilisation. We will use transgenic reporter lines to test the relationship between Wnt signalling and strain in wt and mutant fish. Utilising computational modelling in concert with genetics and live cell imaging we aim to shed light on how OA susceptibility genes affect joint shape and loading, and how chondrocytes respond to strain under normal and mutant conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Chondrocytes from Clinical Grade Embryonic Stem Cells
Funder: Medical Research Council

Abstract: Current clinical treatment for osteoarthritis, which affects 25% of adults over 65 yrs (WHO estimate), is limited to pain relief and there is no treatment able to delay or reverse the condition. Irreversibly damaged joints are eventually replaced by synthetic prostheses, which are successful in older patients (>65), but less so in younger patients whose life expectancy is much greater than that of the prosthesis and revision surgery is less successful. There is therefore a large unmet clinical need for improved treatment for OA. To address this need we developed a protocol to differentiate pluripotent stem cells to chondrogenic cells at high efficiency and these cells which can repair cartilage defects in a rodent model. The protocol is entirely serum free, chemically defined and yields up to 97% chondrogenic cells. We will now adapt this procedure to deliver cells suitable for clinical applications, meeting current Good Manufacturing Practice (cGMP ) standards. We will employ strategies leading to greater cell expansion; apply our refined protocol to a range of clinical grade hESC lines derived in Manchester and in other Centres, evaluating lines for chondrogenic bias. The differentiated cells will be tested for their ability to repair a surgical cartilage defect, without evidence of adverse effects including the generation of ectopic growths or tumours in i) a rat defect model and ii) in a pilot study for a larger animal, the sheep. We will develop and test methods for the clinical delivery and storage of the cells using fibrin gels, evaluating viability and shelf life.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Analysing the cell biology of SNX10 in endosomal sorting and signaling: implications for osteoclast function in osteopetrosis
Funder: Medical Research Council

Abstract: In sorting an array of cargos, for example proteins, lipids, nutrients, and solutes, to a variety of cellular destinations, the endosomal network performs an essential function in numerous processes within the cell. Sorting nexins are an ancient evolutionary conserved protein family that are emerging as key orchestrators of endosomal sorting. In humans, 31 sorting nexins are expressed. For the majority we know very little as to their function. For those that have been studied one common role is emerging: the capture of cargo proteins from lysosomal degradation through sorting into multiple pathways to the plasma membrane and trans-Golgi network. Recently, mutations in the sorting nexin-10 (SNX10) gene have been linked with autosomal recessive osteopetrosis, a genetically heterogenous disorder caused by reduced bone resorption by osteoclasts. Three independent studies, describing 23 patients of Palestinian, Iraqi and North Swedish origin, have revealed a number of nonsense, missense and splicing defects. Patients show a range of severity with no obvious correlation with the specific molecular defect in SNX10. Supporting the in vivo link between disrupted SNX10 function and osteopetrosis are in vitro data that SNX10 is required for osteoclast differentiation and osteoclast resorption. Based on these data, and additional preliminary data, we shall test the following hypothesis: SNX10 functions to assemble an endosome sorting complex that mediates the efficient sorting and cell surface expression of various receptor types, including receptor activator of NF-kB (RANK), that together are required to commit osteoclast lineage cells fordifferentiation to functional osteoclasts, and that for these receptors, loss of SNX10 function leads to adverse endosomal sorting, a resultant decrease in cell surface expression and inability to fully commit to osteoclastogenesis. Clinically this defect in endosomal sorting is manifested as autosomal recessive osteopetrosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: MRC National Survey of Health and Development: hip and spine morphologies from DXA images related to osteoporosis, osteoarthritis and low back pain
Funder: Medical Research Council

Abstract: This project will develop and apply Active Shape Models to dual-energy x-ray absorptiometry (DXA) images of the hip and spine recently acquired for the MRC National Survey of Health and Developmental (NSHD). This cohort was recruited in 1946 and has been followed-up regularly since. They are now approaching the age where diseases associated with ageing are becoming increasingly important. Our specific interests are musculoskeletal disorders, especially osteoarthritis, osteoporosis and low back pain. From the images, mode scores will be derived using Active Shape Modelling, which includes principal components analysis, to provide a quantitative description of the morphology of each joint. Mode scores will be calculated for each image and submitted to the NSHD database. These scores will provide a valuable description of joint shapes in a cross-section of the community at age 65 that can be related to social, behavioural and biomedical data collected over the previous 67 years and will form a useful baseline for future recall of these individuals. Associations between joint shape and life course factors that might affect the shape will be explored using adaptations of existing life course models. These will explore factors such as those related to birth, early and teenage development, body size, activity and strength.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MUSCULOSKELETAL
Title: MICA: Integrated interfacial sensors for assessments of lower limb prosthetics
Funder: Medical Research Council

Abstract: This 2-year project is designed to develop a practical sensor system that can measure pressure and shear stresses at loaded body-support interface. Such a system can be applied in many biomedical areas associated with the design of insoles, matresses, special seating, assitive rehabilitation robotics, orthotics and prosthetics. In lower limb prosthetics, at the human-machine interface, the socket represents the most critical component for an amputee yet to date its effectiveness is largely unknown due to current unavailability of such a monitoring system. Accordingly, poor socket fit is common and leads to stump pain, ulceration, and secondary amputations. We address this unmet need by exploiting a sensor invention with a filed patent application. We propose to integrate the sensors into intelligent lining/interface materials to deliver a practical system that can monitor loads at the critical stump/socket interface. This will be achieved with 3 proposed milestones, objectives and work packages to cover the development stages of simulator apparatus, sensor system validation, clinical validation and optimization towards user centred product profiles. Scientific and clinical rationale underpinning the proposal have been demonstrated by lab and clinical results. A practical rational is demonstrated by the low cost and integral manner of the proposed system. Such a monitoring system is not currently available on the market. Successful delivery will lead to a new generation of interface systems and a stream of by-products that can be used by prosthetists to assess socket fitting quality, which at present is a largely subjective and iterative process. Additional project delivery will enable advanced monitoring and care tools for amputees to timely adjust socket fit preventing stump tissue damage. The proposed technology represents the first step in delivery of the "holy grail" in prosthetics, namely, a fully automatic self-adjusting socket interface for amputees.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL