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 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 Sema3A 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.

愈伤组织重塑受损会显着导致骨质疏松性骨折延迟愈合；然而，其根本机制仍不清楚。感觉神经信号在骨修复中起着至关重要的作用。在本研究中，我们旨在研究阻碍骨质疏松性骨折骨重塑的病理机制，特别关注感觉神经信号的作用。我们证明，在卵巢切除 (OVX) 小鼠中，愈伤组织重塑过程中 CGRP ⁺ TrkA ⁺感觉神经元信号传导的丧失与骨愈伤组织内 Cx3cr1 ⁺ iOCs 表达的增加相关。条件性敲除 Cx3cr1 ⁺ iOCs 可恢复 CGRP ⁺ TrkA ⁺感觉神经元，从而实现正常的愈伤组织重塑进展。从机制上，我们进一步证明Cx3cr1 ⁺ iOCs在骨质疏松骨折修复微环境中分泌Sema3A，抑制CGRP ⁺ TrkA ⁺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 CGRP ⁺ TrkA ⁺感觉神经元信号传导的丧失与 Cx3cr1 ⁺ iOC 表达增加之间的关联。总之，通过抑制 Cx3cr1 ⁺ iOCs 活性来增强 CGRP ⁺ TrkA ⁺感觉神经信号传导是治疗骨质疏松性骨折延迟愈合的潜在策略。