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Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models

Author

Listed:
  • Wei Qiao

    (The University of Hong Kong
    The Johns Hopkins University School of Medicine
    The University of Hong Kong-Shenzhen Hospital
    The University of Hong Kong)

  • Dayu Pan

    (The Johns Hopkins University School of Medicine
    Tianjin Medical University General Hospital)

  • Yufeng Zheng

    (Peking University)

  • Shuilin Wu

    (Tianjin University)

  • Xuanyong Liu

    (Chinese Academy of Sciences
    Cixi Center of Biomaterials Surface Engineering)

  • Zhuofan Chen

    (Sun Yat-sen University)

  • Mei Wan

    (The Johns Hopkins University School of Medicine)

  • Shiqin Feng

    (Tianjin Medical University General Hospital)

  • Kenneth M. C. Cheung

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Kelvin W. K. Yeung

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Xu Cao

    (The Johns Hopkins University School of Medicine)

Abstract

Bone formation induced by divalent metal cations has been widely reported; however, the underlying mechanism is unclear. Here we report that these cations stimulate skeleton interoception by promoting prostaglandin E2 secretion from macrophages. This immune response is accompanied by the sprouting and arborization of calcitonin gene-related polypeptide-α+ nerve fibers, which sense the inflammatory cue with PGE2 receptor 4 and convey the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone for new bone formation. Moreover, either macrophage depletion or knockout of cyclooxygenase-2 in the macrophage abolishes divalent cation-induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in the sensory nerves eliminates the osteogenic effects of divalent cations. Thus, our study reveals that divalent cations promote bone formation through the skeleton interoceptive circuit, a finding which could prompt the development of novel biomaterials to elicit the therapeutic power of these divalent cations.

Suggested Citation

  • Wei Qiao & Dayu Pan & Yufeng Zheng & Shuilin Wu & Xuanyong Liu & Zhuofan Chen & Mei Wan & Shiqin Feng & Kenneth M. C. Cheung & Kelvin W. K. Yeung & Xu Cao, 2022. "Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28203-0
    DOI: 10.1038/s41467-022-28203-0
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    Cited by:

    1. Fengwei Zhang & Wei Qiao & Ji-an Wei & Zhengyi Tao & Congjia Chen & Yefeng Wu & Minghui Lin & Ka Man Carmen Ng & Li Zhang & Kelvin Wai-Kwok Yeung & Billy Kwok Chong Chow, 2024. "Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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