Jiang Y, Chen J, Guo S, Cui W, Zhou Y, Chen X, Wang D, Wang X, Li L, Xu Y
Department of Periodontics, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, China PRC.
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China PRC.
J Dent Res. 2025 Sep;104(10):1105-1115. doi: 10.1177/00220345251329330. Epub 2025 May 1.
Oxidative stress has emerged as a critical player in the development and progression of periodontitis. Transient receptor potential melastatin 2 (TRPM2) is a crucial oxidative stress sensor, while its role in periodontitis and its relationship with the oxidative stress microenvironment remains poorly understood. The objective of this research is to unravel the mechanism by which reactive oxygen species (ROS) activate the TRPM2 channel, driving osteoclast differentiation and eventually leading to bone degradation in periodontitis. By doing so, we aim to provide novel insights into the initiation, progress, and potential treatment methodologies for bone loss instigated by periodontitis. In this study, our results revealed significant upregulation of TRPM2 expression in inflamed periodontal tissues and a close alliance with osteoclast differentiation. First, significant upregulation of TRPM2 in periodontitis, with a clear association with osteoclast differentiation, was observed based on the GEO database. In addition, enhanced levels of TRPM2 and oxidative stress markers were evident in samples from both periodontitis patients and the mouse model of periodontitis. Importantly, the ablation of TRPM2 distinctly alleviated alveolar bone resorption in periodontitis-affected mice. In vitro assays concluded that ROS-induced TRPM2 activation fostered osteoclast differentiation and amplification of osteoclast-related genes. Moreover, RNA-seq results illuminated a close alliance of TRPM2 with osteoclast differentiation, oxidative phosphorylation, mitochondrial inner membrane, and mitochondrial protein complexes. Further validation indicated that damaged mitophagy could overproduce ROS to activate TRPM2 as a positive regulator of osteoclast differentiation via the Ca/NFATc1 signaling pathway. Finally, we conducted in vivo and in vitro interventions using a TRPM2 inhibitor and found that the inhibition of TRPM2 significantly alleviated bone loss induced by periodontitis. Consequently, our results suggest that TRPM2 plays a crucial role in triggering osteoclast differentiation in periodontitis's oxidative stress microenvironment, signifying a potential therapeutic target for prevention and treatment of bone erosion induced by periodontitis.
氧化应激已成为牙周炎发生和发展的关键因素。瞬时受体电位香草酸亚型2（TRPM2）是一种重要的氧化应激传感器，但其在牙周炎中的作用及其与氧化应激微环境的关系仍知之甚少。本研究的目的是揭示活性氧（ROS）激活TRPM2通道，驱动破骨细胞分化并最终导致牙周炎中骨吸收的机制。通过这样做，我们旨在为牙周炎引发的骨质流失的起始、进展和潜在治疗方法提供新的见解。在本研究中，我们的结果显示TRPM2在炎症性牙周组织中的表达显著上调，并且与破骨细胞分化密切相关。首先，基于GEO数据库观察到牙周炎中TRPM2显著上调，且与破骨细胞分化明显相关。此外，在牙周炎患者和牙周炎小鼠模型的样本中，TRPM2和氧化应激标志物的水平均明显升高。重要的是，TRPM2的缺失明显减轻了牙周炎小鼠的牙槽骨吸收。体外实验得出结论，ROS诱导的TRPM2激活促进了破骨细胞分化和破骨细胞相关基因的扩增。此外，RNA测序结果表明TRPM2与破骨细胞分化、氧化磷酸化、线粒体内膜和线粒体蛋白复合物密切相关。进一步验证表明，受损的线粒体自噬可通过Ca/NFATc1信号通路过度产生ROS来激活TRPM2，作为破骨细胞分化的正调节因子。最后，我们使用TRPM2抑制剂进行了体内和体外干预，发现抑制TRPM2可显著减轻牙周炎诱导的骨质流失。因此，我们的结果表明，TRPM2在牙周炎氧化应激微环境中触发破骨细胞分化中起关键作用，这意味着它是预防和治疗牙周炎引起的骨侵蚀的潜在治疗靶点。
