25-Hydroxyvitamin D-3-enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus

Background and Objective: Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus-associated periodontitis), and 25-hydroxyvitamin D-3 (25VD(3)) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T-cell protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a potential downstream protein of the 25VD(3)/vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus-associated periodontitis. Material and Methods: Porphyromonas gingivalis-infected db/db mice were treated with 25VD(3). Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor-, interferon- and interleukin-6) were determined at the time of killing. The effect of PTPN2 on human OKF6-TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6-TERT2 cells were determined through western blot and immunohistochemical analyses. Results: After 25VD(3) treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD(3)-enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD(3) increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. Conclusion: PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD(3) treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus-associated periodontitis.