Journal Article

Boosting Sensory Nerve‐to‐Bone Interactions Enhances Hedgehog Mediated Calvarial Bone Repair

Xing, Xin, James, Aaron W., Archer, Mary, Zhou, Myles, Rao, Chunbao, Chen, Austin Z., Li, Zhao, Zhu, Manyu, Cherief, Masnsen, Du, Beicheng

2026

Overview

Any person that has broken a bone can attest to the existence of sensory innervation of the skeleton. Beyond afferent functions, sensory neurons have been implicated in the orchestration of bone repair via the release of neuroregulatory signals. Yet, these neurosecretory effects have principally been deciphered through loss‐of‐function studies. Indeed, the potential therapeutic benefit of boosting nerve‐to‐bone interactions remains cursorily studied. Here, using a mouse calvarial bone defect model, pharmacologic activation of TrkA with a small molecule partial agonist induced bone‐associated nerve ingrowth and significantly improved calvarial bone healing. Single‐cell RNA sequencing analysis of cells from the defect site revealed shifts in cluster proportions, with enrichment of immune cell populations in TrkA agonist‐treated mice. Within the skeletal cell lineage, TrkA agonism enhanced osteoblast differentiation while suppressing fibroblastic differentiation. Pathway analysis showed increased Hedgehog signaling activity, and interactome analyses between trigeminal ganglia sensory neurons and skeletal cells implicated Hedgehog signaling. The pro‐regenerative effects of TrkA agonism were abolished in conditional knockout mice lacking Smoothened (Smo) in PDGFRα+ skeletal progenitor cells. In summary, boosting sensory nerve signaling enhances membranous bone repair after injury, at least in part via Hedgehog pathway activation in osteoprogenitor cells. Boosting sensory nerve activity via TrkA agonism strongly accelerates calvarial bone repair in adult mice. Furthermore, single‐cell RNA sequencing and neuron–bone interactome analyses identify these sensory neurons as a direct neural source of Hedgehog pathway ligands. Consequently, these ligands drive osteoblast differentiation of skeletal progenitors, enhancing local tissue healing through Smoothened‐dependent signaling.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animals / bone regeneration / Bone Regeneration - drug effects / Bone Regeneration - genetics / Bone Regeneration - physiology / Bones / calvarial defect / Cell adhesion & migration / Cell growth / Cells (biology) / Defects / Differentiation / Disease Models, Animal / Fractures / Ganglia / Genes / Growth factors / Hedgehog Proteins - genetics / Hedgehog Proteins - metabolism / hedgehog signaling / Immune system / Kinases / Leukocytes / Mice / Mice, Knockout / Nerves / Neurons / neuron–bone crosstalk / Receptor, trkA - agonists / Receptor, trkA - metabolism / sensory neuron / Sensory Receptor Cells - metabolism / Signal Transduction / skeletal stem cell / Skull - metabolism / Stem cells / TrkA / Velocity