My laboratory's aim is to discover the mechanisms of collagen cleavage in order to develop new therapies that prevent joint destruction in arthritis. We focus on the collagenases (MMPs-1, -8 and –13), and other enzymes that irreversibly break down fibrillar collagen. I discovered that oncostatin M (OSM) + interleukin 1 (IL-1) dramatically and reproducibly stimulate collagen release from cartilage - a key step in cartilage destruction. MMP-1, -3, -8 and –13 are all upregulated by this cytokine combination along with members of the ADAM (a disintegrin and metalloproteinase) family and can be inhibited by the TIMPs. We showed the importance of collagenase activation in controlling cartilage collagen release and that blocking furin and other serine proteinases prevents such activation.
Gene array analysis of cytokine-treated chondrocytes identified novel genes that highlight potential new mechanisms involved in cartilage breakdown. These include cytokines, proteinases, components of signalling pathways, receptors and cell surface proteins.
My research currently focuses on mechanisms of collagenolysis and the discovery of new substrates for the collagenases. I aim to study mechanisms of disease in osteoarthritis cartilage and investigate the cellular mechanisms of ageing in relation to extra cellular matrix turnover. I will collaborate with other members of the MRC/AR-UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA) to investigate these ageing mechanisms in the other tissues of the joint such as tendon, bone and muscle. Targets identified are investigated in human tissues to relate novel findings to human disease.
arthritis, collagen, MMP, TIMP, connective tissue