NOD2介导损伤相关分子模式（DAMPs）调控骨关节炎软骨退变的作用和机制研究

Osteoarthritis (OA) is the main cause of pain and disability in joint, and has become a public health problem that seriously endangers human health. Chronic inflammation plays an important role in OA, which is activated mainly by DAMPs. DAMPs are commonly existed in osteoarthritic tissues, however, their function and signal transduction mechanisms haven’t been fully investigated. Our previous study showed that the pattern recognition receptor NOD2 is up-regulated in osteoarthritic tissues, and intra-articular injection of adenovirus knockout NOD2 alleviated mouse osteoarthritic cartilage degeneration while independent from its classical ligand MDP. Another potential way to activate NOD2 is DAMPs, so we hypothesized that DAMPs produced by joint tissue damage or aging promote chronic inflammatory response by activating NOD2 and participate in the regulation of OA development. This project intends to construct chondrocytes and synovious macrophage NOD2-cKO mice to further confirm the role of NOD2 in OA . By mouse OA model, we would like to clearly clarify the main tissue cell types of NOD2 signaling, and identify involved DAMPs and their mechanisms that activate NOD2 in synovial fluid of OA patients by liquid chromatography-mass spectrometry, to provide new theoretical and practical basis for the prevention and treatment of osteoarthritis.

骨关节炎（OA）是导致关节疼痛和残障的主要疾病，已成为严重危害人类健康的公共卫生问题。慢性炎症反应在OA中发挥重要作用，而DAMPs是激活慢性炎症的主要分子。DAMPs在OA组织中广泛存在，但其功能和信号转导机制尚未完全明确。我们的前期研究发现，模式识别受体NOD2在OA组织中表达上调，关节腔注射腺病毒敲除NOD2能够明显缓解小鼠OA软骨退变，而这一作用不依赖于其经典配体MDP。能够激活NOD2的另一途径便是DAMPs，因此我们推测关节组织细胞损伤或老化产生的DAMPs通过激活NOD2促进慢性炎症反应，参与调控OA发生发展。本项目拟构建软骨细胞和滑膜巨噬细胞NOD2-cKO小鼠，通过小鼠OA模型进一步证实NOD2在OA中的作用并明确介导NOD2信号的主要组织细胞类型；通过液相色谱-质谱分析探究OA患者关节液中能够激活NOD2的DAMPs及其机制。以期为骨关节炎防治提供新的理论和实践依据。

研究背景：骨关节炎（OA）是导致关节疼痛和残障的主要疾病，已成为严重危害人类健康的公共卫生问题。慢性炎症反应在OA中发挥重要作用，而DAMPs是激活慢性炎症的主要分子。DAMPs在OA组织中广泛存在，但其功能和信号转导机制尚未完全明确。我们的前期研究发现，模式识别受体NOD2在OA组织中表达上调，关节腔注射腺病毒敲除NOD2能够明显缓解小鼠OA软骨退变，而这一作用不依赖于其经典配体MDP。能够激活NOD2的另一途径便是DAMPs，因此我们推测关节组织细胞损伤或老化产生的DAMPs通过激活NOD2促进慢性炎症反应，参与调控OA发生发展。..研究内容：（1）关节软骨细胞特异性敲除NOD2对小鼠骨关节炎模型疾病的影响。（2）滑膜巨噬细胞特意性敲除NOD2对小鼠骨关节炎模型疾病的影响。（3）骨关节炎疾病过程中激活NOD2的上游DAMPs筛选和效应检测。..重要结果及关键数据：（1）本项目成功建立了关节软骨细胞NOD2条件性敲除小鼠及滑膜巨噬细胞NOD2条件性敲除小鼠。（2）关节软骨细胞特异性敲除NOD2不影响小鼠膝关节正常发育。（3）关节软骨细胞特异性敲除NOD2减轻小鼠骨关节炎软骨退变。..科学意义：该项目所建立的关节软骨细胞NOD2条件性敲除小鼠及滑膜巨噬细胞NOD2条件性敲除小鼠为研究NOD2在关节组织中的具体作用奠定了基础。该项目研究结果证实了敲除NOD2对骨关节炎进展过程中关节软骨的保护作用。