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

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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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82372464)

National Key Research and Development Program of China (2023YFB3810200) Shenzhen Medical Research Fund (D2301004) Shenzhen Science and Technology Program (JCYJ20240813154919025) Open Project of State Key Laboratory of Phytochemistry and Natural Medicines (P2025-KF03X)

Shenzhen Science and Technology Program (JCYJ20240813154916021)

CAS Interdisciplinary Team of "Light of West China" Program (xbzg-zdsys-202405)

Shenzhen Science and Technology Program (SYSPG20241211173922057)

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