Nerve-Bone Interactions in Skeletal Physiology

The skeletal system is intimately innervated by sensory, sympathetic and parasympathetic nerves that regulate bone formation, remodelling and repair. Peripheral nerve fibres penetrate distinct bone compartments—including periosteum, cortical canals and marrow—and release a range of neurotransmitters and neuropeptides to modulate osteoblast and osteoclast activity. Central circuits integrate afferent signals from bone and adjust sympathetic tone to fine-tune skeletal homeostasis. This bidirectional communication supports developmental growth, orchestrates fracture healing and underlies pain perception. Emerging concepts of skeletal interoception highlight how the nervous system senses bone metabolic state and adapts systemic responses. Understanding these pathways offers routes to novel therapies for osteoporosis, delayed union fractures and neuroskeletal disorders, and informs bioelectronic approaches to enhance bone regeneration.

Research from Nature Portfolio

Seminal work has shown that osteoblast‐derived prostaglandin E2 binds EP4 receptors on sensory nerves, triggering a central neural circuit that suppresses sympathetic outflow and promotes bone formation. Ablation of sensory innervation or genetic deletion of EP4 in nerves leads to significant bone loss, whereas local enhancement of prostaglandin E2 restores bone volume. This discovery established a feedback loop linking bone metabolic signals to neural regulation of skeletal homeostasis and paved the way for targeted interventions in bone disorders.

Research from all publishers

Hallmarks of peripheral nerve function in bone regeneration: Detailed mapping of sensory and sympathetic fibres in injured bone reveals that neuropeptides and neurotransmitters coordinate osteogenesis, angiogenesis and immune cell recruitment. Peripheral nerves communicate with mesenchymal progenitors, vascular endothelium and macrophages to drive effective callus formation and restore skeletal integrity.

Inhibition of inflammatory osteoclasts enhances CGRP+TrkA+ signalling in osteoporotic fractures: In osteoporotic models, Sema3A secreted by inflammatory osteoclasts suppresses regeneration of CGRP-positive sensory fibres, delaying callus remodelling. Targeting osteoclast activity reinstates sensory nerve regrowth, restores CGRP+TrkA+ signalling and accelerates healing, identifying nerve–bone signalling as a therapeutic axis for fracture repair in compromised bone.

Neurovascular coupling in bone regeneration: The spatial interplay between nerves and blood vessels underlies coordinated osteogenesis and angiogenesis during repair. Neuronal-derived growth factors regulate vascular sprouting, while endothelial signals support nerve survival. Dual targeting of neural and vascular networks emerges as a promising strategy to enhance clinical bone regeneration.

Nerve-Bone Interactions in Skeletal Physiology publication trend

The graph below shows the total number of articles in nerve-bone interactions in skeletal physiology across all publications each year (not limited to Nature Index journals).

Technical terms

Neuropeptide: Small protein released by neurons that modulates cellular activity in bone and other tissues.

Prostaglandin E2 (PGE2): Lipid mediator produced by osteoblasts that activates sensory nerves to regulate bone formation.

Calcitonin Gene-Related Peptide (CGRP): Sensory neuropeptide promoting bone regeneration and angiogenesis.

Osteoblast: Cell responsible for synthesis and mineralisation of bone matrix.

Osteoclast: Cell specialised in bone resorption during remodelling.

Periosteum: Fibrous layer covering bone surface, richly innervated and vascularised.

EP4 receptor: Prostaglandin E2 receptor on sensory nerves mediating bone–nerve signalling.

References

1. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nature Communications (2019).
2. Hallmarks of peripheral nerve function in bone regeneration. Bone Research (2023).
3. Inhibition of inflammatory osteoclasts accelerates callus remodeling in osteoporotic fractures by enhancing CGRP+TrkA+ signaling. Cell Death & Differentiation (2024).
4. Neurovascular coupling in bone regeneration. Experimental & Molecular Medicine (2022).
5. Deciphering the skeletal interoceptive circuitry to control bone homeostasis. BMEMat (2025).