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bioRxiv · 10.1101/2024.05.21.595143

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

Wang, Y.·Shu, Y.·Tan, Z.·Pan, Z.·Chen, Y.·Wang, J.·He, J.
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Abstract

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.

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Wang, Y., Shu, Y., Tan, Z., Pan, Z., Chen, Y., Wang, J., He, J.. 2024-05-21. Inhibition of Inflammatory Osteoclasts Enhances CGRP+TrkA+ Signaling and Accelerates Callus Remodeling in Osteoporotic Fractures. https://doi.org/10.1101/2024.05.21.595143

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