假体周围骨溶解中成骨细胞自噬的信号通路

Signaling pathway of osteoblast autophagy in periprosthetic osteolysis

背景:最近的证据表明,自噬作为一种细胞自我保护机制,在调节成骨细胞功能和维持成骨细胞稳态方面起着重要作用,其对假体周围骨溶解的治疗与预后存在重要影响。目的:通过总结既往关于成骨细胞自噬机制的研究,为假体周围骨质溶解提供新的治疗思路和潜在的治疗靶点。方法:由第一作者应用计算机检索2015-2022年出版的文献,以“磨损颗粒、假体周围骨溶解、成骨细胞、信号通路、自噬”等为中文检索词检索中国知网、万方和维普数据库;以“wear debris,wear particles,peri^(*)prosthetic osteolysis,PPOL,Aseptic loosening,osteoblast,OB,Signal path,autophagy”等为英文检索词检索PubMed和Web of Science数据库,按照入选标准最终共纳入98篇文章。结果与结论:(1)在假体周围骨溶解中,磨损颗粒诱导的成骨细胞自噬能力的改变对于疾病的发展及转归有着关键性的作用。(2)多种信号通路共同介导成骨细胞自噬的过程,其中关键通路包括AMPK/ULK1/mTOR、核转录因子κB及Pink1/Parkin等,AMPK,mTOR及ULK1三者能够相互调节,共同维持自噬水平的稳定,核转录因子κB通路与自噬之间存在复杂的串扰,PINK1及Parkin在受损线粒体膜表面聚积,诱导线粒体自噬。(3)多条信号通路之间存在串扰,相互影响下构成了复杂的自噬网络,且在不同细胞中,相同自噬通路的激活可能会带来截然不同的影响。(4)磨损颗粒诱导的适度的自噬会减少成骨细胞的凋亡,同时增强其分化及矿化能力,改善假体周围骨溶解的预后;反之,自噬激活的不足或过度都会对成骨细胞带来损害,推动骨溶解的进展;因此,通过药物或者基因靶向调控磨损颗粒诱导的成骨细胞自噬水平可能是假体周围骨溶解治疗的方向之一。

BACKGROUND:Recent evidence suggests that autophagy,as a cell self-protection mechanism,plays an important role in regulating osteoblast function and maintaining osteoblast homeostasis.It has an important influence on the treatment and prognosis of periprosthetic osteolysis.OBJECTIVE:To provide new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis by summarizing previous studies on the autophagy mechanism of osteoblasts.METHODS:The first author used the computer to search the articles published from 2015 to 2022.In Chinese,the search terms“wear particles,periprosthetic osteolysis,osteoblasts,signal pathways,autophagy”were used to search the databases of CNKI,WanFang,and VIP.In English,the PubMed and Web of Science databases were retrieved with“wear debris,wear particles,peri^(*)prosthetic osteolysis,PPOL,aseptic loosening,osteoblast,OB,signal path,autophagy”.A total of 98 articles were included according to the inclusion criteria.RESULTS AND CONCLUSION:(1)In periprosthetic osteolysis,the changes in the autophagy ability of osteoblasts induced by wear particles play a key role in the development and outcome of the disease.(2)A variety of signaling pathways jointly mediate autophagy in osteoblasts,among which the key pathways include AMPK/ULK1/mTOR,nuclear factor-κB,Pink1/Parkin,etc.AMPK,mTOR,and ULK1 can regulate each other and jointly maintain the stability of the autophagy level.There is a complex crosstalk between the nuclear factor-κB pathway and autophagy.PINK1 and Parkin are accumulated on the surface of the damaged mitochondrial membrane,inducing autophagy.(3)There is crosstalk among multiple signaling pathways,which form a complex autophagy network under their mutual influence.Moreover,the activation of the same autophagy pathway in different cells may bring about completely opposite effects.(4)Moderate autophagy induced by wear particles can reduce the apoptosis of osteoblasts,enhance their differentiation and mineralization ability,and improve the prognosis of osteolysis around the prosthesis.On the contrary,insufficient or excessive activation of autophagy will cause damage to osteoblasts and promote the progress of osteolysis.Therefore,targeting the level of autophagy of osteoblasts induced by wear particles through drugs or genes may be one of the directions for the treatment of periprosthetic osteolysis.