Professor Tim Cawston
Dean of Research and William Leech Professor of Rheumatology

Research Interests

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. We 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. We showed the importance of collagenase activation in controlling cartilage collagen release and that blocking furin and other serine proteinases prevents such activation. We also aim to identify proteinases that initiate MMP activation cascades.

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.

Our research now includes investigation of the role of YKL40, identification of proteinases found at the cell surface, discovery of new activation cascades for MMPs, mechanisms of collagenolysis, discovery of new substrates for the collagenases and the effect of drugs on cartilage metabolism. All targets are investigated in human arthritic tissue to relate novel findings to human disease. We aim to study osteoarthritis cartilage to investigate cellular mechanisms of ageing in relation to extra cellular matrix turnover.

Keywords

arthritis