Shu Yuexia, Tan Zhenyu, Pan Zhen, Chen Yujie, Wang Jielin, He Jieming, Wang Jia, Wang Yuan
Laboratory of Key Technology and Materials in Minimally Invasive Spine Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Center for Spinal Minimally Invasive Research, Shanghai Jiao Tong University, Shanghai, China.
Cell Death Differ. 2024 Dec;31(12):1695-1706. doi: 10.1038/s41418-024-01368-5. Epub 2024 Sep 2.
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.
骨痂重塑受损显著导致骨质疏松性骨折愈合延迟；然而，其潜在机制仍不清楚。感觉神经元信号在骨修复中起关键作用。在本研究中，我们旨在探究阻碍骨质疏松性骨折骨重塑的病理机制，尤其关注感觉神经元信号的作用。我们证明，在去卵巢（OVX）小鼠中，骨痂重塑过程中降钙素基因相关肽受体A（CGRPTrkA）感觉神经元信号的丧失与骨痂内Cx3cr1阳性破骨细胞（Cx3cr1iOCs）表达增加相关。条件性敲除Cx3cr1iOCs可恢复CGRPTrkA感觉神经元，使骨痂重塑进程正常化。从机制上讲，我们进一步证明，Cx3cr1iOCs在骨质疏松性骨折修复微环境中分泌信号素3A（Sema3A），抑制CGRPTrkA感觉神经元的轴突再生并抑制神经-骨信号交换，从而阻碍骨重塑。最后，在人类样本中，我们观察到CGRPTrkA感觉神经元信号丧失与Cx3cr1iOCs表达增加之间存在关联。总之，通过抑制Cx3cr1iOCs活性增强CGRPTrkA感觉神经信号是治疗骨质疏松性骨折愈合延迟的一种潜在策略。抑制炎性破骨细胞可增强CGRPTrkA信号并加速骨质疏松性骨折的骨痂重塑。
