Role of TRPM2 in Oxidative Stress–Mediated Bone Loss in Periodontitis

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 Ca²⁺/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.