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

Author

Listed:
  • 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
    University of 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
    University of 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
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • 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, 2024. "Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48255-8
    DOI: 10.1038/s41467-024-48255-8
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    References listed on IDEAS

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