Sensing the skeleton: sensorineural regulation in bone

The traditional view of bone tissue as an inert mechanical scaffold has been fundamentally revised over time. Perhaps nowhere is this more clear than in the emerging field of 'skeletal neuroscience', which has revealed the skeleton to be a densely innervated organ that senses and integrates mechanical, immune and metabolic stimuli. Here, we review recent evidence for bidirectional crosstalk between somatosensory neurons and the bone microenvironment, and highlight how techniques such as whole-tissue clearing, genetic tracing and single-cell transcriptomics have mapped osteo-neural interactions with molecular precision. Nerve growth factor (NGF)-TrkA signalling coordinates somatosensory nerve growth and survival during skeletal development and repair, yet the same pathways can drive pathological nerve sprouting, skeletal pain and disease progression in skeletal pathologies ranging from osteoarthritis to heterotopic ossification and bone malignancies. We further discuss neuro-immune-bone interactions, conserved neuroregulatory mechanisms in the skeleton, and emerging neuromodulatory strategies. Finally, we identify topics for future investigation, including the effects of age-related neural decline on the skeleton, sex differences in skeletal innervation and bone pain, and translational gaps between rodent and human biology, that may guide the design of precision medicine interventions.