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

Wei QiaoDayu PanYufeng ZhengShuilin WuXuanyong LiuZhuofan ChenMei WanShiqing FengKenneth M C CheungKelvin Wai-Kwok YeungXu Cao
Published in: Nature communications (2022)
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 PGE 2 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.
Keyphrases
  • ionic liquid
  • immune response
  • adipose tissue
  • mesenchymal stem cells
  • oxidative stress
  • signaling pathway
  • bone marrow
  • nitric oxide
  • gene expression
  • binding protein
  • nitric oxide synthase