Autophagy mediated CoCrMo particle-induced peri-implant osteolysis by promoting osteoblast apoptosis

Abstract

Wear particle-induced osteolysis is the leading cause of aseptic loosening, which is the most common reason for THA (total hip arthroplasty) failure and revision surgery. Although existing studies suggest that osteoblast apoptosis induced by wear debris is involved in aseptic loosening, the underlying mechanism linking wear particles to osteoblast apoptosis remains almost totally unknown. In the present study, we investigated the effect of autophagy on osteoblast apoptosis induced by CoCrMo metal particles (CoPs) in vitro and in a calvarial resorption animal model. Our study demonstrated that CoPs stimulated autophagy in osteoblasts and PIO (particle-induced osteolysis) animal models. Both autophagy inhibitor 3-MA (3-methyladenine) and siRNA of Atg5 could dramatically reduce CoPs-induced apoptosis in osteoblasts. Further, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Moreover, 3-MA also prevented osteoblast apoptosis in an antiautophagic way when tested in PIO model. Collectively, these results suggest that autophagy plays a key role in CoPs-induced osteolysis and that targeting autophagy-related pathways may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.

Keywords:

• aseptic loosening
• autophagy
• osteoblasts
• osteolysis
• wear particles

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Supplemental Material

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Funding

This work was supported by the National Science Fund for Distinguished Young Scholars (81025019), the National Basic Research Program of China (2012CB517603), the National High Technology Research and Development Program of China (2014AA020707), the Program for New Century Excellent Talents in University (NCET-13–0272), the National Natural Science Foundation of China (31370977, 31400671, 31271013, 31170751, 31200695, 51173076, 91129712 and 81572111), the Department of Orthopedics Clinical Research Center of Jiangsu Province, China (BL2012002), the Key Project of the Chinese Ministry of Education (108059), the Ph.D. Programs Foundation of the Ministry of Education of China (20100091120020, 20130091110037), the Graduate Education Innovation Project of Jiangsu Province (KYZZ15_0045), the Scientific Research Foundation of Graduate School of Nanjing University (2015CL12) and the Nanjing University State Key Laboratory of Pharmaceutical Biotechnology Open Grant (KF-GN-201409).