生理平流剪切应力通过COX-2/MMPs信号通路参与机械损伤诱发骨关节炎发病的作用机制研究

项目名称： 生理平流剪切应力通过COX-2/MMPs信号通路参与机械损伤诱发骨关节炎发病的作用机制研究

项目编号： No.31300777

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 王璞

作者单位： 东北大学

项目金额： 24万元

中文摘要： 机械损伤激活基质金属蛋白酶(MMPs)是造成骨关节破坏，进而导致骨关节炎(OA)发生的关键环节。平流剪切应力作为机械损伤的主要致病因素在OA恶化过程中发挥了至关重要的作用，然而其具体机制尚不清楚。鉴于此，本项目拟采用平流剪切应力处理人软骨细胞T/C-28a2，结合信号传导的相关研究手段，研究平流剪切应力激活的COX-2及其代谢产物调控MMPs表达的信号通路，明确COX-2/MMPs信号通路在介导平流剪切应力诱发人软骨细胞炎症反应过程中的作用机制。同时，利用平流剪切应力自发诱导Hartley豚鼠OA发病的特性，分析COX-2抑制剂类药物-塞来昔布对COX-2信号通路中各分子活性及MMPs表达的影响，从而确证MMPs作为OA发病的最终执行者，在OA发生发展过程中的核心作用。通过本项目的实施，建立和完善体内外OA研究的技术体系，揭示OA发生、发展的分子机制，为OA的预防、诊断和治疗提供理论依据。

中文关键词： 平流剪切应力；骨关节炎；环氧合酶-2；前列腺素；基质金属蛋白酶

英文摘要： Mechanical injury produces high hydrostatic stress, tensile strain and fluid flow on articular cartilage, which precipitates in destruction of articular cartilage and development of secondary osteoarthritis (OA). As a consequence of the mechanical damage to articular cartilage, expression of matrix degrading enzymes, such as matrix metalloproteinases (MMPs), are highly induced in chondrocytes, which in turn contribute to the pathology of OA. However, the mechanism remains unknown. Using the human T/C-28a2 chondrocytic cell line as a model system, we demonstrate that prolonged application of high fluid shear to human chondrocytes will induce the expression of MMPs relative to static controls, which was reversed by the treatment of COX-2 inhibitor, NS398. In addition, we will elucidate the mechanisms or signaling pathways that COX-2 regulates MMPs expression in response to lamellar fluid shear stress. More importantly, the biological functions of MMPs on the pathogenesis of OA will be further addressed in the OA model of Hartley guinea pigs. Taking the advantage of high fluid shear stress on cartilage in the OA model of Hartley guinea pigs, the activities of signaling molecules and the expression of MMPs will be determined in celecoxib-treated pigs. As compared with non-treatment pigs, the pivotal roles of MMPs in

英文关键词： Shear stress；osteoarthritis；cyclooxygenase-2；prostaglandins；matrix metalloproteinases