State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases;Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology.
J Dent Res. 2023 Nov;102(12):1376-1386. doi: 10.1177/00220345231195765. Epub 2023 Sep 21.
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.
正畸诱导的炎症性牙根吸收（OIIRR）是正畸治疗的主要医源性并发症，严重威胁着牙齿的寿命和咀嚼功能。破骨细胞被认为是引发 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，成牙骨质细胞是牙骨质中主要的机械反应细胞，对压缩应力做出反应后被激活，并在局部影响破骨细胞。在这项研究中，我们假设，在引起牙齿移动的生理性压缩力或引起 OIIRR 的病理性压力的不同大小下，作为成牙骨质细胞中关键的机械转导途径的鞘氨醇-1-磷酸（S1P）信号通路可能会调节破骨细胞。在这里，我们展示了较高压缩力的双相效应刺激 S1P 的合成和分泌，而较低的压缩力降低了 IDG-CM6 成牙骨质细胞中的信号。使用来自受力成牙骨质细胞的条件培养基，我们验证了成牙骨质细胞和破骨细胞之间的细胞间通讯，并表明 S1PR1 和 Rac1 的选择性敲低通过 S1P/S1PR1/Rac1 轴在成牙骨质细胞驱动的破骨细胞生成中起作用。最重要的是，该轴的抑制剂的使用减少或防止了 OIIRR 的病理过程。成牙骨质细胞和破骨细胞之间的细胞间通讯机制可能成为 OIIRR 的有前途的治疗靶点。
