Mapping somatosensory afferent circuitry to bone identifies neurotrophic signals required for fracture healing
Mingxin Xu, Zhao Bo Li, Neelima Thottappillil, Masnsen Cherief, Manyu Zhu, Xin Xing, Mario Gomez-Salazar, Chunbao Rao, Sowmya Ramesh, Juliet M. Mwirigi, Ishwarya Sankaranarayanan, Diana Tavares-Ferreira, Chi Zhang, Xue-Wei Wang, Mary Archer, Yun Guan, Robert J. Tower, Patrick Cahan, Theodore J. Price, Thomas Clemens, A. James
Abstract
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 Aβ-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.