Abstract
This study explored the role of transient receptor potential channel melastatin 2 (TRPM2)-mediated activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in osteogenesis during healing of tooth extraction sockets. Tooth extraction socket tissue samples were collected from patients with or without periodontitis. In a TRPM2 knockout mouse model of socket healing, mice with or without periodontitis and their wild-type littermates were used for comparing the socket healing phenotypes. Micro-computed tomography imaging, three-dimensional reconstruction of the sockets, and hematoxylin and eosin staining for histopathologic analysis were performed. Immunofluorescence, immunohistochemistry, and Western blot analysis were used for evaluation of protein expression; the mRNA levels were evaluated by quantitative RT-PCR. Osteogenic, chondrogenic, and adipogenic differentiation potential of human bone marrow mesenchymal stem cells (BMMSCs) was evaluated. Calcium deposition was evaluated using Alizarin Red S staining. NLRP3 and CASP1 were up-regulated in tooth sockets of periodontitis patients. NLRP3 knockdown promoted the osteogenic differentiation of maxillary BMMSCs under inflammatory conditions. TRPM2 was up-regulated in the tooth extraction socket tissue of periodontitis. Inhibiting TRPM2 expression mitigated the NLRP3 inflammasome and its deleterious effect on osteogenesis. Activation of the TRPM2 ion channel regulated osteogenesis of BMMSCs under inflammatory conditions via Ca2+ influx, the mitochondrial dynamics, and pyroptosis. Targeting the TRPM2/Ca2+/NLRP3 axis could be beneficial in the healing process of the tooth extraction sockets of patients with periodontitis.