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

Wei Qiao, Dayu Pan, Yufeng Zheng, Shuilin Wu, Xuanyong Liu, Zhuofan Chen, Mei Wan, Shiqin Feng, Kenneth M. C. Cheung, Kelvin W. K. Yeung () and Xu Cao ()
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Wei Qiao: The University of Hong Kong
Dayu Pan: The Johns Hopkins University School of Medicine
Yufeng Zheng: Peking University
Shuilin Wu: Tianjin University
Xuanyong Liu: Chinese Academy of Sciences
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
Kelvin W. K. Yeung: The University of Hong Kong
Xu Cao: The Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28203-0

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