Sensory nerve-derived CGRP controls osteoclastogenesis by limiting macrophage bioenergetics in bone repair

Sensory nerves act as intrinsic effectors of the inflammatory response, whose role in osteoimmunology during healing remains poorly defined. Using a bone healing model with sensory denervation, it’s shown that sensory nerves protect bone repair by suppressing excessive osteoclastogenesis.

During the acute inflammatory phase, sensory nerves are upstream regulators of macrophage activation. At the molecular level, calcitonin gene-related peptide (CGRP), a sensory neuron–derived neuropeptide, is identified to modulate macrophage activation by restricting key functions such as migration, phagocytosis, and pro-inflammatory cytokine production. Importantly, CGRP rapidly constrains adenosine triphosphate (ATP) synthesis with limited mitochondrial respiration in activating macrophages, accompanied by downregulating genes associated with oxidative phosphorylation and mitochondrial complex components.