The histone demethylase KDM5C aggravates titanium particle-induced osteolysis by promoting macrophage inflammation...

Wear debris-induced periprosthetic osteolysis (PPO) is a major complication following total joint arthroplasty, leading to implant failure. Macrophage inflammatory response and osteoclastogenesis play important roles in bone destruction and resorption in PPO. KDM5C (lysine-specific demethylase 5 C), a H3K4 demethylase, functions as a transcriptional repressor in various biological processes, including immune response, energy metabolism, and neurodevelopment. However, its role in PPO pathogenesis remains unclear. In this study, we observed elevated KDM5C expression in macrophages exposed to Titanium (Ti) particles in vitro. Genetic inhibition of KDM5C attenuated Ti particle-induced upregulation of pro-inflammatory factors and reduced the release of inflammatory cytokines. Moreover, KDM5C knockdown suppressed osteoclast differentiation, as evidenced by the decrease in osteoclast number and osteoclast-specific marker expression. Mechanistically, KDM5C was found to repress NFE2L2 transcription by decreasing H3K4 trimethylation (H3K4me3) at its promoter. Inhibition of NFE2L2 abolished the protective effects of KDM5C knockdown on macrophage inflammation and osteoclast differentiation. The calvarial osteolytic model in vivo also demonstrated that silencing KDM5C alleviated Ti particle-induced bone destruction, inflammation, and osteoclastogenesis. Collectively, these findings suggest that KDM5C promotes macrophage inflammatory response and osteoclastogenesis by repressing NFE2L2 transcription through decreasing H3K4me3 levels. It may offer a novel insight into the potential therapeutic target for wear particle-induced osteolysis.