Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Tongling Huang, Zhaocheng Lu, Zihui Wang, Lixin Cheng, Lu Gao, Jun Gao, Ning Zhang, Chang-An Geng, Xiaoli Zhao, Huaiyu Wang, Chi-Wai Wong, Kelvin W. K. Yeung, Haobo Pan, William Weijia Lu and Min Guan ()
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Tongling Huang: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Zhaocheng Lu: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Zihui Wang: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Lixin Cheng: Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital
Lu Gao: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Jun Gao: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Ning Zhang: Shantou University Medical College
Chang-An Geng: Kunming Institute of Botany, Chinese Academy of Sciences
Xiaoli Zhao: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Huaiyu Wang: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Chi-Wai Wong: Guangzhou Huazhen Biosciences
Kelvin W. K. Yeung: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Haobo Pan: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
William Weijia Lu: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Min Guan: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.

Date: 2024
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DOI: 10.1038/s41467-024-48255-8

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