Inhibition of Inflammatory Osteoclasts Enhances CGRP+TrkA+Signaling and Accelerates Callus Remodeling in Osteoporotic Fractures

Impaired callus remodeling significantly contributes to the delayed healing of osteoporotic fractures; however, the underlying mechanisms remain unclear. Sensory neuronal signaling plays a crucial role in bone repair. In this study, we demonstrate that in ovariectomized (OVX) mice, the loss of CGRP + TrkA + sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1 + iOCs expression within the bone callus. Conditional knockout of Cx3cr1 + iOCs restored CGRP + TrkA + sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1 + iOCs secrete seme3A in the osteoporotic fracture repair microenvironment, inhibiting CGRP + TrkA + sensory neurons’ axonal regeneration and suppressing nerve-bone signaling exchange, thus hindering bone remodeling. Lastly, in human samples, we observed an association between the loss of CGRP + TrkA + sensory neuronal signaling and increased expression of Cx3cr1 + iOCs. In conclusion, enhancing CGRP + TrkA + sensory nerve signaling by inhibiting Cx3cr1 + iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures.