Orthodontically induced inflammatory root resorption (OIIRR) is the major iatrogenic complication of orthodontic treatment, seriously endangering tooth longevity and impairing masticatory function. Osteoclasts are thought to be the primary effector cells that initiate the pathological process of OIIRR; however, the cellular and molecular mechanisms responsible for OIIRR remain unclear. Our previous studies revealed that cementocytes, the major mechanically responsive cells in cementum, respond to compressive stress to activate and influence osteoclasts locally. For this study, we hypothesized that the sphingosine-1-phosphate (S1P) signaling pathway, a key mechanotransduction pathway in cementocytes, may regulate osteoclasts under the different magnitudes of either physiologic compressive stress that causes tooth movement or pathologic stress that causes OIIRR. Here, we show a biphasic effect of higher compression force stimulating the synthesis and secretion of S1P, whereas lower compression force reduced signaling in IDG-CM6 cementocytes. Using conditioned media from force-loaded cementocytes, we verified the cell-to-cell communication between cementocytes and osteoclasts and show that selective knockdown of S1PR1 and Rac1 plays a role in cementocyte-driven osteoclastogenesis via the S1P/S1PR1/Rac1 axis. Most importantly, the use of inhibitors of this axis reduced or prevented the pathological process of OIIRR. The intercellular communication mechanisms between cementocytes and osteoclasts may serve as a promising therapeutic target for OIIRR.

中文翻译：

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受力牙骨质细胞通过 S1P/S1PR1/Rac1 轴调节破骨细胞生成。

正畸引起的炎性牙根吸收（OIIRR）是正畸治疗的主要医源性并发症，严重危害牙齿寿命并损害咀嚼功能。破骨细胞被认为是启动 OIIRR 病理过程的主要效应细胞；然而，导致 OIIRR 的细胞和分子机制仍不清楚。我们之前的研究表明，牙骨质细胞是牙骨质中主要的机械响应细胞，它对压缩应力做出反应，从而激活并影响局部破骨细胞。在本研究中，我们假设 1-磷酸鞘氨醇 (S1P) 信号通路（牙骨质细胞中的关键机械转导通路）可能在导致牙齿移动的生理压应力或导致 OIIRR 的病理应力的不同强度下调节破骨细胞。在这里，我们展示了较高压力刺激 S1P 合成和分泌的双相效应，而较低压力则减少 IDG-CM6 牙骨质细胞中的信号传导。使用来自强制加载的牙骨质细胞的条件培养基，我们验证了牙骨质细胞和破骨细胞之间的细胞间通讯，并表明选择性敲低 S1PR1 和 Rac1 在通过 S1P/S1PR1/Rac1 轴驱动的牙骨质细胞驱动的破骨细胞生成中发挥作用。最重要的是，该轴抑制剂的使用减少或阻止了 OIIRR 的病理过程。牙骨质细胞和破骨细胞之间的细胞间通讯机制可能作为 OIIRR 的一个有前途的治疗靶点。