The role of COX-2 in skeletal development and osteoarthritis

骨性关节炎（OA）是最常见的关节炎类型，也是残疾的主要原因。研究表明 前列腺素生物合成中的关键酶环氧化酶-2（考克斯-2）的表达水平在前列腺增生症中是高水平的， OA影响的软骨增加。但是，考克斯-2表达增加在OA中的作用还不清楚， 学得很好。此外，小鼠模型研究增加考克斯-2的功能意义 在骨关节炎软骨中的表达目前不可用。我们建立了考克斯-2转基因小鼠 该模型可以在任何细胞类型中实现C 0X-2表达。使用这个小鼠模型， 先前显示考克斯-2的表达增加会干扰骨骼发育。这个目标 本研究旨在探讨考克斯-2在OA发病机制中的作用，并探讨其可能的分子机制。 机制使用软骨细胞特异性，诱导型考克斯-2转基因小鼠和细胞文化模式在这 因此，我们假设考克斯-2表达的增加通过以下途径参与OA的发病机制： 去调节炎性细胞因子/蛋白酶的表达。目标1.我们将产生软骨细胞特异性的， 诱导型考克斯-2转基因小鼠的建立oxed C 0X 2小鼠至Cot 2a 1CreERT小鼠。目标2.使用 在这种小鼠模型中，我们将分析自发和自发性软骨变性的发作和进展， 实验诱导的OA模型。此外，我们还将测定细胞外基质（ECM）的水平。 在考克斯-2过表达的原代软骨细胞中的组分。目标3. V\/e将分析 C 0X-2过表达软骨和原代软骨细胞中炎性细胞因子/蛋白酶表达。在 此外，还研究了考克斯-2对软骨细胞增殖、凋亡和分化的影响以及dov/nstream 将研究考克斯-2的信号通路。拟议的研究将深入了解 考克斯-2在OA发病机制中的作用，可能有助于开发预防和治疗OA的策略。 OA。

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.