RIPK3在磨损颗粒激活巨噬细胞PRRs/NLRP3信号通路引起人工关节无菌性松动中的作用机制

Arthroplasty is the most effective treatment for end-stage osteoarthropathy. Over the world, more than 13 million cases of arthoplasty were performed each year, while the longevity of artificial joint is limited largely due to the aseptic loosening, which doesn’t have any effective pharmaceutical treatment yet. The applicant has conducted in-depth researches in Germany and in China under the support of several NSFC funds. She found that wear particles from prostheses could activate macrophages via PRRs to produce inflammatory cytokines, which activate osteoclasts, and result in periprosthetic osteolysis, which is the main cause of aseptic loosening of artificial joint. Recently, we have revealed that activation of NLRP3 was the crucial part in the production of inflammatory cytokines in macrophages stimulated by wear particles. Latest researches reported that activation of NLRP3 inflammasome assembled by NLRP3, ASC and pro-Caspase-1 was the key process in production of inflammatory cytokines in macrophages, while RIPK3 (receptor-interacting protein kinase 3) was the pivotal regulating target in the activation of NLRP3 inflammasome. However, it remains unclear whether RIPK3 has a role in aseptic loosening of artificial joint. On the basis of previous researches, this project will explore the role of RIPK3 in activation of macrophage PRRs/NLRP3 signaling pathway and secretion of inflammatory cytokine induced by wear particles via in vivo and in vitro experiments, and provide a new horizon in the prevention and treatment of aseptic joint loosening.

人工关节置换术是治疗终末期骨关节疾病最有效的方法，全球每年超过1300万例，而术后假体无菌性松动严重制约了人工关节的使用寿命，目前却无有效的药物来防治它。本人在德国留学期间及回国后国家自然基金资助下的研究发现：来源于假体的磨损颗粒通过经典激活巨噬细胞PRRs释放的前炎症因子可进一步激活破骨细胞导致假体旁骨溶解，这是人工关节无菌性松动的主要原因。我们近期发现颗粒刺激巨噬细胞PRRs产生前炎症因子的过程中NLRP3起了重要作用。最近有研究提出激活NLRP3与ASC和Caspase-1前体组装成的NLRP3炎性小体是巨噬细胞产生前炎症因子的关键，而RIPK3是调控该小体激活的关键靶点，但其在人工关节无菌性松动中的作用尚无文献报道。本研究将在以往的基础上，通过体内外实验探讨RIPK3在磨损颗粒激活巨噬细胞PRRs/NLRP3信号通路的作用，为防治人工关节无菌性松动开辟新的思路。

人工关节置换术是治疗终末期骨关节疾病的最有效方法，但无菌性松动严重制约了假体远期寿命。既往研究表明磨损颗粒能激活巨噬细胞的模式识别受体PRRs，如TLRs、NLRs等，从而产生促炎因子，继而激活破骨细胞引起假体周围骨溶解，最终导致人工关节无菌性松动。在前期研究基础上，本项目目前已按研究计划顺利完成，并有如下发现：1、在磨损颗粒刺激的巨噬细胞中，RIPK3可参与到NLRP3炎性小体的组装中，并促进巨噬细胞线粒体凋亡释放活性氧，从而介导IL-1β的释放；2、敲低RIPK3可抑制钛颗粒刺激巨噬细胞NLRP3炎性小体的组装，降低IL-1β分泌水平；3、通过小鼠颅骨溶解模型的建立，我们进一步证明RIPK3敲低慢病毒的注射可以缓解钛颗粒引起的颅骨溶解情况，说明RIPK3在磨损颗粒激活巨噬细胞引起人工关节无菌性松动的过程中起重要作用。但上述实验抑制RIPK3的表达并未能完全阻止炎症因子表达上调，其他PRRs（包括NLRs和TLRs）相关分子可能参与磨损颗粒激活巨噬细胞引起人工关节无菌性松动的过程，因此我们通过后续研究发现ZBTB20正向调控钛颗粒诱导巨噬细胞的促炎效应，而USP14/NLRC5和NOD2对钛颗粒诱导的骨溶解起重要的负性调节作用。综上所述，PRRs通路在磨损颗粒激活巨噬细胞引起人工关节无菌性松动的过程中起重要作用，其中RIPK3是磨损颗粒通过PRRs引起人工关节无菌性松动的关键分子。

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