Inhibition of inflammatory osteoclasts accelerates callus remodeling in osteoporotic fractures by enhancing CGRPTrkA signaling.

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 aimed to investigate the pathological mechanisms hindering bone remodeling in osteoporotic fractures, particularly focusing on the role of sensory neuronal signaling. We demonstrate that in ovariectomized (OVX) mice, the loss of CGRPTrkA sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1iOCs expression within the bone callus. Conditional knockout of Cx3cr1iOCs restored CGRPTrkA sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1iOCs secrete Sema3A in the osteoporotic fracture repair microenvironment, inhibiting CGRPTrkA 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 CGRPTrkA sensory neuronal signaling and increased expression of Cx3cr1iOCs. In conclusion, enhancing CGRPTrkA sensory nerve signaling by inhibiting Cx3cr1iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures. Inhibition of inflammatory osteoclasts enhances CGRPTrkA signaling and accelerates callus remodeling in osteoporotic fractures.