Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

A central feature of bone injury is the sensation of pain, transmitted by nociceptive sensory nerves that innervate the skeleton. Indeed skeletal-innervating peripheral neurons are known to regulate skeletal repair and pathophysiology. Here, using retrograde peripheral nerve labeling and single cell RNA sequencing (scRNA-seq), we precisely identify the unique molecular signature of skeletal-innervating sensory neurons and the shifting neuronal transcriptomic landscape after bone fracture. Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated skeletal innervation. Multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding confirmed by in vitro assessments of neuron-to-skeletal mesenchyme interactions. Identification of FGF9 as a novel, neuron-derived skeletal growth factor uncovers a potential target for improving tissue repair.