Research Project
8298313
Osleoarthritis (OA) is the most common type of arthritis and a major cause of disability. Studies have shown that the expression level of cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin biosynthesis, is highly increased in OA-affected cartilages. However., the roie of increased COX-2 expression in OA has not been studied very well. Furthermore, mouse .models to study the functional significance of increased COX-2 expression in osteoarthritic cartiiage are not currently available. We developed a COX-2 transgenic mouse model in which C0X~2 expression can be achieved in any cell type. Using this mouse model, vve have previously shown that increased expression of COX-2 interferes with skeietaf development. The goal of this proposal is to investigate Ihe role of COX-2 in the pathogenesis of OA and address possible molecular mechanisms using chondrocyte-specific, inducible COX-2 transgenic mouse and cel! culture models. In this proposal, vve hypothesize that increased COX-2 expression contributes to the pathogenesis of OA by de-regulating expression of inflammatory cytokines/proteases. Aim 1. We wili generate chondrocyte-specific, inducible COX-2 transgenic mice by crossing CAT-f!oxed C0X2 mice to Cot2a1CreERT mice. Aim 2. Using this mouse model, we will analyze onset and progression of carlilage degenration in spontaneous and experimenlally-induced models of OA. In addition, we will determine the levels of extracellular matrix (ECM) components in COX-2 over-expressing primary chondrocytes. Aim 3. V\/e will analyze the levels of inflammatory cytokine/protease expression in C0X~2 over-expressing cartilage and primary chondrocytes. In addition, the effect of COX-2 on chondrocyte proliferation, apoptosis, and differentiation and the dov/nstream signaling pathways of COX-2 will be investigated. The proposed studies will provide insight into the role of COX-2 in the pathogenesis of OA and may permit development of preventive and therapeutic stratagies for OA.
