Oxphos Drives Biomaterial-Induced Bone Via Balancing Ros-Mediated Osteoclastogenesis

Osteoinductive calcium phosphate ceramics (CaPs) demonstrate significant potential in jaw bone defects with the ability to induce bone formation in ectopic sites, while the molecular mechanism behind remains unclear. This study investigated the critical role of oxidative phosphorylation (OXPHOS) in osteoinductive CaPs-induced bone formation. Bulk RNA-seq of both in vivo and in vitro were performed to analyze the differences between osteoinductive TCPs and non-osteoinductive TCPb, identifying the key pathways OXPHOS. In vitro, macrophages were treated with OXPHOS and reactive oxygen species (ROS) inhibitors and activators, followed by qPCR, immunofluorescence and TRAP staining to analysis M2 macrophage polarization and osteoclast formation. In vivo, an intramuscular implantation model was established, combined with OXPHOS and ROS inhibitor intervention, and osteoclast and bone formation were evaluated via micro-CT and histomorphometry. The in vivo and vitro results demonstrated osteoinductive TCPs promoted M2 macrophage polarization and osteoclastogenesis by significantly upregulated OXPHOS with maintaining moderate level of ROS. OXPHOS inhibition led to ROS overaccumulation, suppressing osteoclast formation and bone formation. Excessive ROS suppression or overactivation impaired these processes. Oxidative phosphorylation activation played key roles in driving biomaterial-induced bone formation by enhancing osteoclastogenesis via balancing ROS. These findings provided a theoretical foundation for optimizing bone regeneration strategies by regulating OXPHOS-ROS axis.