Somatosensory nerves induce the pathologic response to physis injury

Somatosensory neurons are crucial for detecting a diverse repertoire of stimuli, including in skeletal tissues in which sensations of pain, pressure, and position are transmitted. Trauma to the physis often lead to pathologic "bony bar" formation, impeding normal growth of the skeleton. The role of somatosensory nerves in detecting and in turn regulating such an event is entirely unknown. Here, we observed prominent sensory nerve growth within the injured physis in mouse and human tissues corresponding to domains of NGF expression. Two independent methods to inhibit TrkA (Tropomyosin Receptor Kinase A) signaling significantly reduced nerve sprouting and attenuated pathologic bony bar formation, while converse experiments using neural conditioned medium treated organ cultures showed the opposing effects. Somatosensory nerve retrograde tracing and single cell RNA sequencing (scRNA-Seq) identified the precise neural transcriptome evoked by physis injury. Corresponding scRNA-Seq of injured growth plates implicated PTN neuroregulatory signaling in growth plate pathology. Finally, FDA-approved long acting bupivicaine may be used to prevent pathological innervation and ossification of the growth plate after injury. These findings suggest that targeting somatosensory nerves could offer new strategies to treat pain and optimize patient outcomes after growth plate injury.