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.
A is the most common degerierative joint disease in the U.S. and the leading cause of disability in the elderly. Increased COX-2 expression is observed in OA-affected cartilages. However, the functional significance of increased COX-2 expression in OA has not been understood. This study will provide mechanistic insight into the role of COX-2 in the pathogenesis of OA and has the potential to indetifiy novel targets for prevention and treatment of OA.
|Kim, Joohwee; Shim, Minsub (2015) Prostaglandin F2Î± receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation. Biochim Biophys Acta 1853:500-12|
|Chun, Kyung-Soo; Shim, Minsub (2015) EP2 Induces p38 Phosphorylation via the Activation of Src in HEK 293 Cells. Biomol Ther (Seoul) 23:539-48|