Title: Obesity-associated joint inflammation in patients with osteoarthritis: The role of long non coding RNAs
Funder: Versus Arthritis

Abstract: Background Obesity is associated with greater synovial joint inflammation, which is an important factor in both the onset and the progression of osteoarthritis (OA). Therefore, understanding how the obesity-associated inflammation in the joint is regulated may lead to the development of novel anti-inflammatory therapeutics, which could modify OA progression, or prevent disease onset in “at risk” obese individuals. We have demonstrated that long non coding RNAs (lncRNAs) are regulators of the inflammatory response. Critically, our recent studies have identified several lncRNAs that are associated with inflammatory synovial tissue from obese patients with OA, and which modulate the secretion of key pro-inflammatory cytokines that are known to promote cartilage degeneration. We hypothesise that these “inflammation-associated” lncRNAs are central regulators of inflammation in the obese OA synovial joint, and that dysregulated lncRNA activity mediates OA joint degeneration in patients who are obese. Focus and objectives This proposal will determine The relationship between the synovial tissue expression of “inflammation-associated” lncRNAs with adiposity and joint inflammation in patients with OA; The functional role and genes regulated by lncRNAs in synovial fibroblasts in mediating the inflammatory response; The mode-of-action of a lncRNA by identifying its RNA binding proteins; Whether modulation of lncRNA activity in the joint via intra-articular injection of a novel LNA inhibitor mitigates OA disease in a murine model of OA fed a high fat diet. Proposed techniques The expression and localisation of “inflammation-associated” lncRNAs in the synovial tissue from normal-weight and obese knee and hip OA patients (n=18) will be determined by qRTPCR and in-situ hybridisation. Synovial tissue will be assessed for inflammatory markers by histochemistry and synovial fluid pro-inflammatory cytokines measured by ELISA and Luminex. LncRNA expression will be compared to non-OA and RA synovium (n=18). Loss of function studies using LNA inhibitors (Exiqon) and siRNA will determine lncRNA function and mode-of-action in primary human and murine synovial fibroblasts. The DMM model of OA, with mice fed a high fat diet, will determine the in vivo disease-modifying efficacy of a novel lncRNA modulator. Exploitation of the research results Results will be disseminated to commercial, academic, patient and public beneficiaries. For academics, results will be presented at national and international meetings, and published in high impact peer-reviewed journals. To reach public sector and clinical beneficiaries, we will engage with clinical collaborators and service providers via our three national centres of excellence, the MRC-ARUK Centre for Musculoskeletal Ageing, the ARUK Rheumatoid Arthritis Pathogenesis Centre of Excellence and the ARUK Pain Centre in order to highlight the research outputs and the clinical implications. Engagement with the Birmingham Rheumatology Research Patient Partnership (R2P2) will facilitate dissemination to patient groups. To exploit the commercial potential of our results we will engage with the University of Birmingham’s Technology Transfer Team to determine IP and commercial development opportunities and strategies. The University has its own External Commercialisation Board, which includes leading industry experts. This board is linked to the University's own dedicated commercialisation company, Alta Innovations, who support the patent process and facilitate commercial opportunities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL