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.
This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout Shi, H. & Chen, M. The brain–bone axis: unraveling the complex interplay between the central nervous system and skeletal metabolism. Article PubMed PubMed Central Google Scholar Chen, Z., Luo, Z., Greenblatt, M.
Neural regulation of bone: from central neural circuits to peripheral innervation of the skeletal stem cell niche. Article CAS PubMed PubMed Central Google Scholar Xia, R. et al. Autonomic nervous system in bone remodeling: from mechanisms to novel therapies in orthopedic diseases.
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Eph-ephrin signaling mediates cross-talk within the bone microenvironment. Skeletal interoception and prospective application in biomaterials for bone regeneration. Nerves in bone: the silent partners.
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