Targeting <scp>H3K18</scp> Lactylation to Regulate <scp>BMP9</scp> Expression and Enhance Osteogenic Differentiation of Periodontal Ligament Stem Cells Under Inflammatory Conditions

BACKGROUND: Periodontitis is characterized by periodontal ligament and alveolar bone destruction. Bone morphogenetic protein 9 (BMP9) is essential for periodontal tissue regeneration. This study investigates the impact and underlying mechanism of BMP9 on osteogenic differentiation. METHODS: Periodontal ligament stem cells (PDLSCs) were treated with lipopolysaccharide (LPS) to simulate an inflammatory environment in vitro. Osteogenic differentiation was subsequently assessed. We further examined how sodium lactate (NaLa) and 2-deoxy-D-glucose (2-DG) modulated histone lactylation and BMP9 expression. For the in vivo study, experimental periodontitis was induced in rats, followed by local administration of NaLa or BMP9 inhibition. After 30 days, the maxillae were collected and analyzed by micro-computed tomography (micro-CT) and histological staining. RESULTS: LPS treatment significantly downregulated BMP9 expression and impaired osteogenic differentiation in PDLSCs. NaLa enhanced H3K18 lactylation at the BMP9 promoter, increasing BMP9 expression and improving osteogenic differentiation. Conversely, 2-DG inhibited glycolysis, reducing H3K18 lactylation and BMP9 expression. BMP9 overexpression partially restored osteogenic differentiation in LPS-treated PDLSCs. In vivo, we found that inhibition of BMP9 could effectively induce alveolar bone loss in rats with experimental periodontitis. CONCLUSIONS: Modulating lactate metabolism to enhance H3K18la levels and BMP9 expression could be a novel therapeutic strategy for promoting periodontal tissue regeneration in inflammatory conditions.