Cyclic mechanical stress promotes osteogenic differentiation of periodontal ligament stem cells via KAT2A-mediated succinylation of WDR5.

Orthodontics promotes tooth movement and periodontal reconstruction by regulating osteogenic differentiation and osteoclast resorption. This study aimed to investigate the effect of orthodontic force during orthodontics on osteogenesis of periodontal ligament stem cells (PDLSCs) and the underlying mechanism. Cyclic mechanical stress was applied on PDLSCs, and osteogenic differentiation was analyzed using quantitative real-time polymerase chain reaction, immunoblotting, alkaline phosphatase (ALP) staining, and ALP activity determination. The succinylation of WDR5 mediated by KAT2A was evaluated using immunoblotting, immunoprecipitation, and cycloheximide chase experiment. The results showed that cyclic mechanical stress promotes PDLSC osteogenic differentiation in a time-dependent manner. Additionally, the mechanical stress increased total succinylation levels and upregulated KAT2A expression. KAT2A promoted the succinylation of WDR5 and stabilized WDR3 protein. Rescue experiments indicated that KAT2A knockdown or WDR5 overexpressed reversed osteogenesis of PDLSCs mediated by mechanical stress or KAT2A knockdown, respectively. In conclusion, KAT2A promotes osteogenic differentiation of cyclic mechanical stress-induced PDLSCs by succinylating WDR5. The findings suggest a novel regulatory mechanism in the orthodontic process.