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

Tongling Huang, Zihui Wang, Lu Gao, Jun Gao, Zhaocheng Lu, Pengda Li, Chon Him Choy, Zhuolei Yuan, Yanting Zhong, Chang-An Geng, Huaiyu Wang, Kelvin W K Yeung, Bin Li, Haobo Pan, Di Chen, Min Guan

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. · pubmed

Paper

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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Research summary

The paper claims that targeting adipocyte ESRRA can alleviate osteoarthritis by interrupting the C3-CFD-MAC cascade. This research is relevant as it addresses the underlying mechanisms linking metabolic dysfunction and aging-related osteoarthritis, potentially offering insights into therapies that could mitigate age-related diseases.

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