IRF4 Suppresses Osteogenic Differentiation of Periodontal Ligament Stem Cells by Activating IL‐18 Signaling Pathway in Periodontitis

Abstract The present study aims to investigate the role of interferon regulatory factor 4 (IRF4) in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and analyze the underlying signaling of these processes. In this study, IRF4 is upregulated in periodontitis periodontal ligament tissues, as compared to healthy periodontal ligament tissues. IRF4 knockdown increases cell proliferation, decreases levels of tumor necrosis factor‐alpha, interleukin‐6, and interleukin‐8, enhances osteogenic activity, and increases the expression of RUNX family transcription factor 2, Collagen I, and Osteocalcin in PDLSCs. The opposite results are observed in IRF4 overexpressed PDLSCs. Additionally, GSEA shows that IRF4 activates the interleukin‐18 (IL‐18) signaling pathway. The expressions of IL‐18, B‐cell translocation gene 2, interleukin‐1beta, and caspase‐3 are decreased by IRF4 knockdown, while increased by IRF4 overexpression. IL‐18 overexpression eliminates the promoting effect of IRF4 knockdown on osteogenic differentiation of PDLSCs. In conclusion, IRF4 suppresses osteogenic differentiation of PDLSCs by activating the IL‐18 signaling pathway.