Mitochondrial OXPHOS integrates immunometabolic cascade for bone regeneration via coupled ATP production and ROS homeostasis

  • Redox Biol. 2026 Jun 22:95:104272. doi: 10.1016/j.redox.2026.104272.
Jingrong Chen  1 ,  Ping He  1 ,  Jiayi Gu  1 ,  Jingqi Wu  1 ,  Yuxiao Liu  1 ,  Wei Lei  1 ,  Tong-Chuan He  2 ,  Liwen Zheng  1 ,  Joost D de Bruijn  3 ,  Huipin Yuan  4 ,  Hongmei Zhang  5 ,  Mingzheng Li  6
Affiliations
  • 1. The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, PR China; Chongqing Key Laboratory of Oral Diseases, Chongqing, 401147, PR China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, PR China; Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China.
  • 2. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, 60637, USA.
  • 3. Kuros Biosciences BV, Prof. Bronkhorstlaan 10, Bilthoven, 3723 MB, the Netherlands.
  • 4. Kuros Biosciences BV, Prof. Bronkhorstlaan 10, Bilthoven, 3723 MB, the Netherlands; Huipin Yuan's Lab, Chengdu, 610000, PR China. Electronic address: [email protected].
  • 5. The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, PR China; Chongqing Key Laboratory of Oral Diseases, Chongqing, 401147, PR China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, PR China; Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China. Electronic address: [email protected].
  • 6. The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, PR China; Chongqing Key Laboratory of Oral Diseases, Chongqing, 401147, PR China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, PR China; Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China. Electronic address: [email protected].
PMID: 42335846 DOI: 10.1016/j.redox.2026.104272
Abstract

Osteoinductive calcium phosphate ceramics (CaPs) hold great promise for bone repair, yet the metabolic principles governing their efficacy are poorly defined. Here, we identify mitochondrial Oxidative Phosphorylation (OXPHOS) as an early and indispensable pathway activated specifically by an osteoinductive tricalcium phosphate (TCPS) in material-induced bone formation. Our findings demonstrate that OXPHOS critically governs the M2 macrophage-osteoclast axis for bone formation by regulating both cellular energy supply and Reactive Oxygen Species (ROS) homeostasis. Disrupting either function-by inhibiting OXPHOS (reducing ATP production) or by disrupting ROS balance (including ROS scavenging or accumulation)-uncouples this metabolic-immunological cascade and abrogates bone formation. Our work establishes mitochondrial OXPHOS as a central metabolic hub that integrates bioenergetics with ROS balance to orchestrate material-induced bone formation via M2 macrophage polarization-osteoclastogenesis axis. Consequently, these insights provide a rational basis for therapeutic modulation of the immunometabolic cascade in bone regeneration, via strategies designed to co-activate OXPHOS and fine-tune ROS dynamics.

Keywords
Macrophage polarization; Osteoclast; Osteoinductive materials; Oxidative phosphorylation; Reactive oxygen species.
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