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，也是导致残疾的主要原因。研究表明， 前列腺素生物合成的关键酶环氧合酶-2(COX-2)的表达水平很高。 骨性关节炎影响的软骨组织中含量增加。然而，环氧合酶-2在骨性关节炎中表达增加的原因尚未得到证实 学得很好。此外，用小鼠模型研究COX-2升高的功能意义 目前还不能在骨关节炎的角质层中表达。我们培育了一只COX-2转基因小鼠 可以在任何细胞类型中实现C0X~2表达的模型。使用此鼠标模型，VVE拥有 以前的研究表明，COX-2的表达增加干扰了skeietaf的发育。这样做的目的是 建议研究COX-2在骨性关节炎发病机制中的作用，并探讨可能的分子机制。 使用软骨细胞特异的、可诱导的COX-2转基因小鼠和CEL！文化典范。在这 建议，VVE假设COX-2表达增加通过以下方式参与了OA的发病 去调节炎性细胞因子/蛋白的表达。目标1.我们将产生软骨细胞特异性的， Cat-f！oxC0X2小鼠与Cot2a1CreERT小鼠杂交可诱导COX-2转基因小鼠。目标2.使用 在这个小鼠模型中，我们将分析自发性和自发性Carlilage退行性变的发生和发展 实验诱导的骨性关节炎模型。此外，我们还将测定细胞外基质(ECM)的水平 原代软骨细胞中高表达COX-2组分。目标3.V\/e将分析 炎性细胞因子/蛋白水解酶在C0X~2高表达软骨和原代软骨细胞中的表达在……里面 此外，COX-2对软骨细胞增殖、凋亡和分化的影响以及对Dov/nstream的影响 将对COX-2的信号通路进行研究。拟议的研究将提供对以下角色的洞察 COX-2在骨性关节炎发病机制中的作用 骨关节炎。

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.