Somatosensory nerves drive pathologic bony bar formation after physis injury through pleiotrophin signaling in mouse models

Somatosensory neurons detect a diverse repertoire of stimuli, including in skeletal tissues, in which sensations of pain, pressure, and position are transmitted. Trauma to the physis often leads to pathologic "bony bar" formation, impeding normal growth of the skeleton. The role of somatosensory nerves in detecting and, in turn, regulating physis injury is unknown. Here, we observed prominent sensory nerve growth within the injured physis in mouse and human tissues corresponding to domains of nerve growth factor (NGF) expression. Two independent methods to inhibit tropomyosin receptor kinase A (TrkA) signaling reduced nerve sprouting and attenuated pathologic bony bar formation, whereas conversely sensory neural conditioned medium-treated organ cultures demonstrated the opposing effects. Somatosensory nerve retrograde tracing and single-cell RNA sequencing (scRNA-seq) identified a sensorineural transcriptome evoked by physis injury in mice. Corresponding scRNA-seq of injured mouse growth plates implicated pleiotrophin (PTN) signaling in pathologic growth plate ossification, a finding confirmed by ex vivo organ culture and in vivo knockout in sensory ganglia. Last, FDA-approved long-acting bupivacaine prevented pathological innervation and ossification of the growth plate after injury. These findings suggest that targeting somatosensory nerves could offer previously unrecognized strategies to treat pain and prevent pathologic ossification to optimize patient outcomes after growth plate injury.