Loss of cartilage extracellular matrix (ECM) is a central event in the pathogenesis of osteoarthritis (OA). Reduced levels of synthesis, qualitative changes in molecular structure and enhanced enzymatic degradation contribute to the changes seen in OA Cartilage. Cytokines are major regulators of the balance between anabolic and catabolic responses in articular chondrocytes and a large number of cytokines are known to modulate chondrocyte functions. Interleukin-1 (IL-1) is the cytokine which has received most attention as a catabolic factor in cartilage. It inhibits ECM synthesis, stimulates the production of proteases, can reduce the expression of protease inhibitors and stimulates the production Of proinflammatory cytokines, prostaglandins and nitric oxide. Different approaches are being pursued to inhibit IL-1 production or block IL-1 binding to its receptor in the development of new interventions for arthritis. Intracellular events which mediate effects of IL-1 and other catabolic factors on gene expression are of potential therapeutic interest. However, information on signal transduction in chondrocytes is very limited. In previous studies we have examined gene expression in chondrocytes and defined subsets of IL-1 responsive genes which are regulated by different second messengers. These results demonstrated that of all signaling pathways examined, tyrosine kinase activation is the most critical event in regulation of gene expression by catabolic factors in chondrocytes and also required for the activation of mitogen activated protein (MAP) kinase. With these preliminary findings the present application is focused on the following specific aims: (i) MAP kinase and MAP kinase subfamilies in chondrocytes and mechanisms of activation; (ii)The role of Ras chondrocyte activation by catabolic stimuli and identification of guanine nucleotide exchange factor; (iii) Molecular identity of IL-1 activated tyrosine kinase in chondrocytes; (iv)Effects of tyrosine kinase inhibition on catabolic responses in chondrocytes and cartilage organ cultures. Tyrosine kinase inhibition and in vivo models of cartilage degradation. These studies will generate insight into mechanisms involved in cartilage degradation and provide a basis for improved concepts on osteoarthritis pathogenesis and treatment.
