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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Kirshner, Annette G
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University of South Carolina at Columbia
Schools of Arts and Sciences
United States
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Kim, Joohwee; Shim, Minsub (2015) Prostaglandin F2α 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