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Sensory neuronal signaling plays a crucial role in bone repair. In this study, we aimed to investigate the pathological mechanisms hindering bone remodeling in osteoporotic fractures, particularly focusing on the role of sensory neuronal signaling. We demonstrate that in ovariectomized (OVX) mice, the loss of CGRP<jats:sup>+<\/jats:sup>TrkA<jats:sup>+<\/jats:sup> sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1<jats:sup>+<\/jats:sup>iOCs expression within the bone callus. Conditional knockout of Cx3cr1<jats:sup>+<\/jats:sup>iOCs restored CGRP<jats:sup>+<\/jats:sup>TrkA<jats:sup>+<\/jats:sup> sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1<jats:sup>+<\/jats:sup>iOCs secrete Sema3A in the osteoporotic fracture repair microenvironment, inhibiting CGRP<jats:sup>+<\/jats:sup>TrkA<jats:sup>+<\/jats:sup> sensory neurons\u2019 axonal regeneration and suppressing nerve\u2013bone signaling exchange, thus hindering bone remodeling. Lastly, in human samples, we observed an association between the loss of CGRP<jats:sup>+<\/jats:sup>TrkA<jats:sup>+<\/jats:sup> sensory neuronal signaling and increased expression of Cx3cr1<jats:sup>+<\/jats:sup>iOCs. In conclusion, enhancing CGRP<jats:sup>+<\/jats:sup>TrkA<jats:sup>+<\/jats:sup> sensory nerve signaling by inhibiting Cx3cr1<jats:sup>+<\/jats:sup>iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures.<\/jats:p>","DOI":"10.1038\/s41418-024-01368-5","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T12:02:25Z","timestamp":1725278545000},"page":"1695-1706","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Inhibition of inflammatory osteoclasts accelerates callus remodeling in osteoporotic fractures by enhancing CGRP+TrkA+ signaling"],"prefix":"10.1038","volume":"31","author":[{"given":"Yuexia","family":"Shu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-4074","authenticated-orcid":false,"given":"Yujie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jielin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieming","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6832-6371","authenticated-orcid":false,"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,2]]},"reference":[{"key":"1368_CR1","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","volume":"393","author":"JE Compston","year":"2019","unstructured":"Compston JE, McClung MR, Leslie WD. 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