Wang Han, Cai Jingwen, Chen Linxin, Chen Sihang, Yang Xinhan, Chen Zhonghan, Xu Linyu
Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
Institute of Stomatology & Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
FASEB J. 2025 Mar 15;39(5):e70446. doi: 10.1096/fj.202403234RR.
Orthodontically induced inflammatory root resorption (OIIRR) poses a significant clinical challenge, as excessive orthodontic force shortens tooth longevity by impairing cementoblast-mediated cementum mineralization and promoting root resorption. Cementoblasts, essential for mineralized cementum formation and resistance to resorption, exhibit altered mechanosensitivity and mechanotransduction under orthodontic force, yet the role of mitophagy in this process remains poorly understood. In this study, we investigated how the S1PR1/mitophagy axis modulates cementoblast mineralization and OIIRR progression. The in vivo orthodontic loading model revealed that heavy compression force triggered OIIRR and impaired cementoblast mineralization along with suppression of mitophagy in cementoblasts by downregulating PINK1 and PARKIN expression. The in vitro experiments further confirmed that heavy compression force increased reactive oxygen species (ROS) levels, disrupted mitochondrial membrane potential (MMP), and inhibited mitophagy in OCCM30 cells, thereby impairing their mineralization capacity. Mechanistically, S1PR1 upregulation activated mitophagy, which in turn restored cementoblast mineralization under heavy compression force. Moreover, pharmacological activation of S1PR1 with SEW2871 alleviated OIIRR in vivo. These findings highlight the pivotal role of the S1PR1/mitophagy axis in maintaining cementoblast function and mineralization under orthodontic force, offering novel insights into the molecular mechanisms underlying OIIRR and suggesting potential therapeutic strategies to prevent OIIRR during orthodontic treatment.
正畸诱导的炎性牙根吸收（OIIRR）是一个重大的临床挑战，因为过大的正畸力会损害成牙骨质细胞介导的牙骨质矿化并促进牙根吸收，从而缩短牙齿寿命。成牙骨质细胞对矿化牙骨质的形成和抗吸收至关重要，在正畸力作用下表现出机械敏感性和机械转导的改变，但线粒体自噬在这一过程中的作用仍知之甚少。在本研究中，我们探究了S1PR1/线粒体自噬轴如何调节成牙骨质细胞矿化和OIIRR进展。体内正畸加载模型显示，重度压力会引发OIIRR并损害成牙骨质细胞矿化，同时通过下调PINK1和PARKIN的表达抑制成牙骨质细胞中的线粒体自噬。体外实验进一步证实，重度压力会增加活性氧（ROS）水平，破坏线粒体膜电位（MMP），并抑制OCCM30细胞中的线粒体自噬，从而损害其矿化能力。从机制上讲，S1PR1上调激活了线粒体自噬，进而在重度压力下恢复了成牙骨质细胞矿化。此外，用SEW2871对S1PR1进行药理激活可在体内减轻OIIRR。这些发现突出了S1PR1/线粒体自噬轴在正畸力作用下维持成牙骨质细胞功能和矿化中的关键作用，为OIIRR的分子机制提供了新见解，并提出了在正畸治疗期间预防OIIRR的潜在治疗策略。
