Sensory Nerve‐Derived CGRP Controls Osteoclastogenesis by Limiting Macrophage Bioenergetics in Bone Repair

ABSTRACT Bone healing is a tightly orchestrated, multiphase process that requires coordinated interactions between immune cells and skeletal cells. 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 and mitochondrial respiration in activating macrophages, accompanied by downregulation of genes associated with oxidative phosphorylation and mitochondrial complex components. Following the metabolic alterations, macrophages exposed to CGRP show attenuated osteoclastogenic capacity, with decreased secretion of multiple key factors that support osteoclast differentiation and survival. Together, these findings indicate a neuro–immune–metabolic axis in bone healing, where sensory nerve–derived CGRP influences macrophage bioenergetics and thereby contributes to osteoimmunoligical regulation. It emphasizes the potential of incorporating sensory signals into therapeutic strategies, particularly those targeting immunometabolism in bone regeneration.