Nalp3炎性体在职业因素致膝骨性关节炎中的作用及机制

Work-related knee osteoarthritis(OA) is an important disease which reduces labor force and causes disability. Poor working posture and weight lifting at workplace were reported to be main risk factors for knee OA although the mechanism of OA is still unclear. In this project, we plan to evaluate the role of Nalp3 in the pathogenesis of knee OA induced by squatting or kneeling and weight carrying or lifting at workplaces through three researches. In the animal experiment, knee bending and weight carrying will be stimulated in two separate groups. The Nalp3 and related inflammation cytokines in above animals and animals with anti-Nalp3 will be determined through western-blot, RT-PCR and con focal laser scanning microscope metrology system. The results of Nalp3 and cytokines of several groups will be compared. The possible role of Nalp3 in the development OA induced by knee bending and weight carrying will be analyzed. In a case-control study of OA cases from occupational workers, we will evaluate load of knee movement muscles though QEC tables and determine Nalp3 and related inflammation cytokines in their peripheral blood and articular cavity. The results will used to evaluate the role of Nalp3 in the development of OA. At last, a cohort of workers with poor working posture or weight lifting in one company will be established. We will determine knee muscle load using electromyography based on work posture and weight lifting in different job titles. The knee load will be estimated for each subject by combing knee muscle load and work years in different job titles. The relationship between knee load and levels of Nalp3 or related inflammation cytokines, and changes of knee joint or OA will be analyzed after follow-up of the cohort. This project will provide new knowledge for the mechanism of OA and possible new target for the OA prevention and treatment.

职业因素引起的膝骨性关节炎是降低劳动力和致残的重要疾病，不良工作体位姿势和负重是其重要发病原因，但发病机制仍不清楚，本项目拟探讨Nalp3炎性体在膝关节弯曲姿势和负重致膝关节损伤及骨性关节炎中的作用，采用动物模型分别模拟膝关节弯曲和负重，采用western-blot、RT-PCR、激光共聚焦显微分析系统等比较实验动物和拮抗Nalp3炎性体动物在不同时间段膝关节损伤及炎性反应的异同；通过职业人群膝骨性关节炎病例对照研究，比较骨性关节炎与关节腔和外周血Nalp3炎性体及炎性因子水平的关系，验证Nalp3的作用；建立某企业职业人群队列，应用肌电描记术分析不同工作姿势和负重形成的膝关节负荷，结合工作时间进行个体膝负荷评分，随访分析职业性膝关节负荷对Nalp3及相关炎性因子、膝关节腔狭窄及骨性关节炎的作用，为职业性膝关节损伤机制研究提供新线索，为膝骨性关节炎预防和治疗寻找可能的靶点。

膝关节炎严重影响劳动能力和生活质量，但致病机制仍不清楚。本项目通过动物和细胞实验证实Nalp3 炎性体在膝关节炎中的作用，拮抗Nalp3 可以减缓膝关节炎发展。通过大样本职业人群（13906人）分析了膝骨性关节炎的分布，结合工作姿势负荷评估了职业因素对膝骨性关节炎的影响。取得主要成果如下：（1）关节软骨主要成分羟基磷灰石可激活巨噬细胞，引起Nalp3 mRNA和蛋白表达升高，引起Nalp3关键组分Caspase-1水平升高，拮抗Nalp3 炎性体可抑制羟基磷灰石对巨噬细胞Nalp3 炎性体的激活及后续炎性反应（所有P<0.05）；（2）羟基磷灰石直接刺激软骨细胞未引起基质金属蛋白酶水平发生变化，但含Nalp3炎性体的上清液可引起软骨细胞损伤，增加基质金属蛋白酶MMP-3、MMP-13的表达，拮抗巨噬细胞NALP3 炎性体或IL-1β可减弱上述损伤效应（所有P<0.05）。（3）动物实验表明，膝关节半月板副韧带手术后，膝关节病理变化明显，Nalp3和Caspase-1、炎性因子IL-1βmRNA表达水平升高，TNF-α、IL-6等炎性因子水平升高；拮抗Caspase-1或者IL-1β后，病理观察到膝骨性关节炎症缓解，TNF-α、IL-6等炎性因子mRNA表达水平明显下降，差异有统计学意义（所有P<0.05）；（4）研究人群结果显示，退休者膝关节痛和膝骨性关节炎的患病率分别为39.0%和6.7%，在职者膝关节痛患病率超过20%。职业活动中弯腰、弯腰负重、体力负荷大、轮班是膝关节痛和膝骨性关节炎的危险因素。校正潜在混杂因素后，站位（OR：1.18，95%CI：1.09-1.28）和弯腰位（1.20，1.08-1.34），轮班（1.18,1.01-1.38），工龄延长（1.20，1.08-1.34）是膝骨性关节炎的危险因素。在职工人结果类似，弯腰（1.56，1.05-2.33）和弯腰负重（2.90，1.36-6.21），中等体力负荷1.79(1.03-3.11) 和重体力负荷3.22(1.92-5.41)，工龄延长3.25(1.92-5.50)均是膝骨性关炎危险因素。Nalp3 在膝关节炎中的作用尚未见报道，为本项目创新性发现，对于选择膝关节炎的防治靶点有实用价值。在本项目已发表论文5篇（4篇SCI收录），参加国际会议发言2次，培养6名研究生。

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