Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.

骨形成和沉积是由适应性骨重塑中的感觉神经浸润引发的。在这里，我们使用正畸牙齿移动 (OTM) 模型重点研究了感觉神经表达的信号蛋白 3A (Sema3A) 在机械负荷诱导的骨形成和神经退缩中的作用。首先，OTM第三天后骨形成被激活，同时感觉神经减少和痛阈增加。 OTM第3天后，三叉神经节和牙周膜轴突中Sema3A而非神经生长因子(NGF)高表达。此外，体外机械负荷在 24 小时内上调神经元中的 Sema3A，而不是人牙周膜细胞 (hPDLC) 中的 Sema3A。此外，外源性 Sema3A 恢复了机械过载引起的受抑制的牙槽骨形成和 hPDLC 的成骨分化。从机制上讲，Sema3A 通过 ROCK2 途径防止机械过载引起的 F-肌动蛋白过度拉伸，从而维持线粒体融合时的线粒体动力学。因此，Sema3A 在机械负荷诱导的骨形成中表现出双重治疗作用，既作为疼痛敏感镇痛剂，又作为骨形成的正调节剂。