Histone lactylation mediates the regulation of dental follicle cells' senescence driven by RUNX2 during the process of tooth eruption

Abstract Cleidocranial dysplasia (CCD), an autosomal dominant disorder caused by RUNX2 mutation, is characterized by delayed or failed eruption of the permanent teeth; however, the pathogenesis of tooth impaction remains unclear. Tooth eruption is a complex developmental process in which the dental follicle plays a crucial role. Although the dental follicle is known to coordinate osteoclastogenesis and osteogenesis, the precise cellular mechanisms that initiate eruption are still not fully defined. Moreover, how dental follicles activate the signals of tooth eruption and whether the other biological alterations occur in CCD dental follicles have not been reported. Previous work from our group demonstrated that RUNX2 mutations inhibit dental follicle cell senescence in CCD patients. Cellular senescence participates in diverse physiological and pathological processes and is increasingly implicated as a dynamic regulator of morphogenesis and tissue remodeling. This study investigates whether the senescence of dental follicle cells (DFCs) critically mediates tooth eruption and elucidates its underlying regulatory mechanism. Analysis of dental follicle tissues showed a significant reduction in SA-β-gal-positive and P16 INK4a -positive cells in CCD patients compared with healthy controls. Animal studies revealed a progressive accumulation of senescent cells in the dental follicle during normal tooth eruption, whereas this accumulation was suppressed in Runx2 +/− mice, which exhibit delayed tooth eruption. Inhibition of dental follicle senescence via nicotinamide mononucleotide (NMN) in wild-type mice similarly delayed tooth eruption, confirming the functional necessity of DFCs senescence. Mechanistically, RUNX2 knockdown or mutation upregulated HDAC3 expression, which catalyzed histone delactylation, predominantly at H3K18. The reduced H3K18la levels could lead to transcriptional repression of PLAU. Thus, RUNX2 knockdown or mutation suppressed DFCs senescence via the HDAC3/H3K18la/PLAU axis. Collectively, our study reveals that DFCs senescence acts as an important driver of tooth eruption and identifies a novel epigenetic regulatory mechanism involving histone lactylation that regulates cellular senescence mediated by RUNX2.