Mapping somatosensory afferent circuitry to bone identifies neurotrophic signals required for fracture healing

• 成果类型: Article
• 署名作者: Xu, Mingxin; Li, Zhao; Thottappillil, Neelima; Cherief, Masnsen; Zhu, Manyu; Xing, Xin; Gomez-Salazar, Mario; Rao, Chunbao; Ramesh, Sowmya; Mwirigi, Juliet M.; Sankaranarayanan, Ishwarya; Tavares-Ferreira, Diana; Zhang, Chi; Wang, Xue-Wei; Archer, Mary; Guan, Yun; Tower, Robert J.; Cahan, Patrick; Price, Theodore J.; Clemens, Thomas L.; James, Aaron W.
• 署名单位: Johns Hopkins University; Johns Hopkins Medicine; University of Texas System; University of Texas Dallas; Johns Hopkins University; Johns Hopkins Medicine; State University System of Florida; University of South Florida; Johns Hopkins University; Johns Hopkins Medicine; University of Texas System; University of Texas Southwestern Medical Center; Johns Hopkins University; Johns Hopkins Medicine; University System of Maryland; University of Maryland Baltimore
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adr9608
• 发表日期: 2026-01-08
• 页码: eadr9608
• 关键词: NERVE INJURY; regeneration; skin; shh

摘要

The pain associated with bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration. To characterize neuroanatomical circuitry mediating skeletal nociception and regeneration, we profiled dorsal root ganglia (DRG) neurons innervating murine bones using single-cell transcriptomics before and after fracture. CGRP+ and A beta-Field LTMR neurons were the most represented classes of bone-innervating neurons. Dynamic changes in sensory neuron response to injury reflected the phasic nature of bone repair, including expression of morphogens such as Tgfb1, Fgf9, and Shh. Innervation loss resulted in poor bone repair and was associated with defective mesenchymal cell proliferation and osteodifferentiation. Finally, we identified fibroblast growth factor 9 (FGF9) as a major regulator of fracture repair that could be leveraged to promote bone repair.