Targeting adipocyte ESRRA alleviates osteoarthritis via interrupting inter-organelle crosstalk of complement C3-CFD-MAC cascade

  • Bone Res. 2026 Apr 29;14(1):49. doi: 10.1038/s41413-026-00527-3.
Tongling Huang  #  1 ,  Zihui Wang  #  1 ,  Lu Gao  1  2 ,  Jun Gao  1 ,  Zhaocheng Lu  1 ,  Pengda Li  1 ,  Chon Him Choy  3 ,  Zhuolei Yuan  1  2 ,  Yanting Zhong  1  2 ,  Chang-An Geng  4 ,  Huaiyu Wang  5 ,  Kelvin W K Yeung  6  7 ,  Bin Li  8 ,  Haobo Pan  1 ,  Di Chen  5  9 ,  Min Guan  10  11
Affiliations
  • 1. Shenzhen Key Laboratory of Marine Biomaterials, Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. Division of Biosciences, University College London, London, UK.
  • 4. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
  • 5. Center for AI-Driven Medical Research, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 6. Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 7. Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 8. Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, School of Basic Medical Sciences, Interdisciplinary Innovation Center for Nanomedicine, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, China.
  • 9. Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China.
  • 10. Shenzhen Key Laboratory of Marine Biomaterials, Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  • 11. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 42056078 DOI: 10.1038/s41413-026-00527-3
Abstract

Osteoarthritis is an aging-related systemic disease involving the crosstalk of multiple organs/tissues in metabolism and inflammation, yet little is known about the contribution of liver and marrow adipose tissue (MAT). Here we show that MAT-derived complement Factor D (CFD) and component 3 (C3) derived from steatotic liver coordinately drive excessive alternative complement activation, resulting in cartilage damage in mice during aging and metabolic disorders. Mechanistically, estrogen-related receptor α (ESRRA) transcriptionally upregulates CFD responding to bone marrow adipocytes (BMAds) expansion. Inhibition of ESRRA/CFD signaling in BMAds blocks the chondrocyte senescence and catabolism triggered by C3 that is released from steatotic hepatocyte, interrupting C3-CFD-MAC cascade, thereby suppressing ERK1/2 phosphorylation and mitochondrial dysfunction. Adipocyte-specific ablation or pharmacological inhibition of ESRRA reduces CFD levels particularly in adipocyte-rich bone marrow, attenuating osteoarthritis progression in aged mice. Our findings highlight a key liver-MAT-cartilage axis bridged by C3-CFD-MAC pathway, raising the potential for adipocyte ESRRA-targeting therapies for aging-related metabolic osteoarthritis.

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