MITF Regulated Osteoclast Differentiation And Macrophge Polization In Periodontitis

Aim or purpose: To elucidate the role of microphthalmia-associated transcription factor (MITF) in periodontitis and investigate its regulatory mechanisms in M1 macrophage polarization and osteoclast differentiation. Materials and methods: MITF expression was analyzed in human/mouse periodontitis tissues (IHC, RT-PCR). In vivo, MITF knockout/knockdown and ML329 (MITF inhibitor) were used in periodontitis models to evaluate osteoclastogenesis and macrophage polarization. In vitro, Porphyromonas gingivalis lipopolysaccharide (Pg. LPS) and IFN-γ or Receptor activator of NF-κB ligand (RANKL) were used to stimulate bone marrow-derived macrophages (BMDMs) with/without MITF inhibition to verify the regulatory effects of MITF on macrophage polarization, osteoclast differentiation, and mitochondrial function. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to identify potential signaling pathways involved in MITF-mediated periodontitis. Results: Elevated MITF expression was observed in both human and mouse periodontitis tissues. Genetic or pharmacological inhibition of MITF in vivo and in vitro significantly reduced expression of NFATC1, inhibited osteoclast formation and alveolar bone resorption, and downregulated M1 macrophage markers (iNOS, IL-1β) along with NLRP3 expression, effectively attenuating inflammatory responses. Furthermore, GO/KEGG pathway analysis and validation experiments demonstrated that PI3K/AKT was the central pathway in MITF-mediated periodontitis, where MITF knockout suppressed PI3K/AKT signaling, improved mitochondrial function, and attenuated disease progression, all of which were abolished by the agonist 740Y-P. Conclusions: Our study provided the first evidence that MITF modulated periodontitis through PI3K/AKT-mediated mitochondrial regulation, M1 polarization, and osteoclastogenesis. Targeting MITF may represent a promising therapeutic strategy for periodontitis management.