Mitophagy impairment mediates the pathogenesis of CoCrMo particle-induced osteolysis via NLRP3/caspase-1/GSDMD-dependent pyroptosis in macrophages

作者：Xue, Song; Xu, Yiming; Xu, Shenglin; Zhong, Yiming; Ruan, Guangfeng; Ma, Jinzhong; Hu, Yong^*; Ding, Changhai^*; Sang, Weilin^*

来源：Chemical Engineering Journal, 2022, 435: 135115.

DOI：10.1016/j.cej.2022.135115

• CoCrMo
• Osteoclastogenesis
• Mitophagy
• Reactive oxygen species
• Pyroptosis

Wear particles derived from implant surfaces are the important factors causing periprosthetic osteolysis (PPO), which is the main reason for total joint revision. To date, the specific pathogenesis of PPO remains largely unknown, and developing new therapeutic strategies is urgently necessary. Our study indicated the most clinically common cobalt-chromium-molybdenum (CoCrMo) wear particles (CoPs) activated macrophages and further accelerated osteoclastogenesis. Subsequently, we put emphasis on the pathologic change in macrophages after CoPs stimulation. Meaningfully, high-concentration CoPs induced reactive oxygen species (ROS) accumulation in macrophages and activated NOD-like receptor pyrin domain-containing 3 (NLRP3)-dependent pyroptosis, promoting the release of cytokines such as IL-18, IL-1 beta and HMGB1, and subsequent formation of extracellular inflammatory microenvironment, which is crucial for osteoclastogenesis. More interestingly, transmission electron microscopy and flow cytometry results revealed that there were accumulation of endamaged mitochondria in high-concentration CoP-challenged macrophages, which accelerated intracellular ROS accumulation and mediated NLRP3-dependent pyroptosis. Mechanismly, high-concentration CoPs induced macrophage mitophagy impairment and the loss of mitochondrial membrane potential via inhibiting PINK1/Parkin signalling pathway. Furthermore, by subcutaneous injection of salidroside and/or CY-09 in situ significantly delayed CoP-induced mice calvaria osteolysis. Collectively, this study demonstrates a novel mechanism underlying the pathogenesis of PPO and provides a potential therapy avenue.

• 单位
  上海交通大学; 安徽医科大学; 南方医科大学; y; 河北医科大学; 1