磨损微粒诱导的成骨细胞内质网应激在人工关节假体无菌性松动发病过程中的作用研究

Prosthesis aseptic loosening is the leading cause of joint replacement failure, and there is no prevention and cure for this disease. A mount of researches indicate that the wear particles have tight connection with local inflammation and apoptosis, which result in osteolysis in the end. However, we know very little about the specific mechanism and pathway by which wear particles initiate and regulate the inflammation and apoptosis. Our early work revealed that wear particles could make endoplasmic reticulum stress in macrophages and the latter could release inflammation factors to media osteolysis. Moreover, after the application of the inhibitor of endoplasmic reticulum stress, the inflammation was down-regulated and osteolysis stopped. Based on the background, we plan to study the endoplasmic reticulum stress in the osteoblasts in three levels: clinical sample detection, cytology test, and animal model test, in order to investigate its role in the course of around prosthesis osteolysis, and to make it clear that how the endoplasmic reticulum stress in the osteoblasts regulated the local inflammation and apoptosis signal pathway. Explore the difference of cytological reaction among the wear particles with different size and different material quality. Discover the molecular and cellular mechanism of prosthesis aseptic loosening and propose the potential treatment strategy and drug target for the clinic practice.

人工关节假体无菌性松动严重影响了关节置换的疗效，并无满意的预防和治疗方法。大量研究表明磨损微粒与局部炎症和细胞凋亡以及骨溶解有着密切的关联，但对于磨损微粒引发和调控局部炎症和调亡的具体机制和途径尚不清楚。我们前期的工作发现，磨损微粒作用于巨噬细胞，可诱导后者产生内质网应激，分泌炎性因子，引起骨溶解，使用了内质网应激抑制剂后，炎症因子释放显著减少，骨溶解得到缓解。基于以上背景，我们从临床样本检测、细胞学试验、动物模型试验三个层次，对成骨细胞内质网应激在假体周围骨溶解过程中起的作用进行深入研究，确定磨损微粒诱导成骨细胞内质网应激的机制及其在假体无菌性松动发生发展中的作用，明确成骨细胞内质网应激介导假体周围炎症和调亡的信号通路，探索不同大小与材质的磨损微粒在该细胞学反应中的差异性，揭示假体无菌性松动始动及转归的分子和细胞机制，为临床逆转或治疗关节置换术后无菌性松动提供新的治疗策略和药物靶点。

人工关节假体无菌性松动严重影响了关节置换的疗效，并无满意的预防和治疗方法。大量研究表明磨损微粒与局部炎症和细胞凋亡以及骨溶解有着密切的关联，但对于磨损微粒引发和调控局部炎症和调亡的具体机制和途径尚不清楚。我们前期的工作发现，磨损微粒作用于巨噬细胞，可诱导后者产生内质网应激，分泌炎性因子，引起骨溶解，使用了内质网应激抑制剂后，炎症因子释放显著减少，骨溶解得到缓解。但骨量的变化是一个成骨与溶骨的动态平衡，它们分别由成骨细胞与破骨细胞作为执行细胞。因此，我们对成骨细胞内质网应激在假体周围骨溶解过程中起的作用进行了深入的研究。分别从临床样本检测、细胞学试验、动物模型试验三个层次进行研究，明确了成骨细胞内质网应激介导假体周围炎症和调亡的信号通路，探索了不同大小与材质的磨损微粒在该细胞学反应中的差异性，部分揭示了假体无菌性松动始动及转归的分子和细胞机制，为临床逆转或治疗关节置换术后无菌性松动提供新的治疗策略和药物靶点。