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In this project we aim to systematically identify epigenetic mechanisms that underlie and control the complex stem cell and inflammatory environment in bone that leads to destruction of bone tissue in arthritis and other musculoskeletal conditions. Identification of these epigenetic factors will aid in understanding of disease biology and carries the potential to develop novel therapeutics that could stop inflammation and possibly reverse bone destruction.

WHY IS THIS IMPORTANT?

Introduction of novel therapeutic approaches for treatment of rheumatoid arthritis such as anti-TNF therapy, have greatly improved the outcome and helped patients, but they do not cure disease. Although current antirheumatic therapy inhibits both bone erosion and inflammation, repair of existing bone lesions, albeit physiologically feasible, occurs rarely. Lack of repair is due, at least in part, to active suppression of bone formation by proinflammatory cytokines. We believe that identification of epigenetic mechanisms have the potential that would enable or promote bone regeneration, eventually even stop inflammation, is clinically desirable and constitutes a new frontier in drug discovery in inflammatory arthritis.

HOW ARE WE DOING IT?

Mesenchymal stem cells (MSC) are the progenitors of multiple cell lineages including osteoblasts, chondrocytes, adipocytes and myocytes and are found in large numbers in the bone marrow and the outer surfaces of bones. Osteoblasts, derived from MSC, are the major cellular component of bone and are responsible for the formation of bone. Bones are dynamic structures, with constant re-absorption by osteoclasts and new bone formation by osteoblasts. Any disruption of this equilibrium can lead to weakened bones and impair the ability to repair bone damage.

THE RELATIONSHIPS BETWEEN AGEING, INFLAMMATION AND RHEUMATIC DISEASE

Ample evidence suggests that a combination of age and osteoimmunological factors underpins rheumatic disease. For example, the incidence of rheumatic disease increases with age, the immune system ages prematurely in rheumatoid arthritis, and bone loss is frequently observed in systemic inflammatory conditions such as rheumatoid arthritis. This is coupled through a block in differentiation of mesenchymal stem cells (MSCs) to osteoblasts by inflammatory cytokines. Interestingly, the increase of these same cytokines is associated with the chronic low-grade inflammation seen with age, suggesting a clear relationship between the immune system, inflammation, adult stem cells and their ability to maintain bone homeostasis.