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

ABSTRACT 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.