METTL1 Aggravates Periodontitis Progression by Inhibiting Osteoblast Differentiation via m7G modification of SEMA4D.

OBJECTIVE

Periodontitis is a chronic inflammatory disease that severely affects oral and general health. N7-methylguanosine (m7G) methylation plays critical roles in regulating gene expression and cellular functions. Methyltransferase-like 1 (METTL1), a core component of the m7G methyltransferase complex, has been implicated in various diseases, but its role in periodontitis remains unclear.

METHODS

Lipopolysaccharide (LPS)-induced HPDLSCs were used in vitro experiments to evaluate the effects of METTL1 on osteogenic differentiation (ALP activity, ARS staining) and inflammation (TNF-α, IL-1β, IL-6 levels). In vivo experiments employed a mouse model of periodontitis. Alveolar bone loss was evaluated using micro-CT, and inflammatory responses were analysed histologically and through cytokine quantification. Mechanistic studies included m7G modification assays, luciferase reporter assays, RNA immunoprecipitation (RIP), and mRNA stability assays.

RESULTS

METTL1 was upregulated in LPS-induced HPDLSCs and a mouse model of periodontitis. METTL1 knockdown enhanced osteogenic differentiation and reduced pro-inflammatory cytokine levels in HPDLSCs. In the mouse model, METTL1 knockdown alleviated alveolar bone loss, reduced inflammatory cell infiltration, and restored bone density parameters. Mechanistically, METTL1 regulated SEMA4D expression through m7G modification. SEMA4D overexpression reversed the effects of METTL1 knockdown, and mutation of the m7G site in SEMA4D attenuated the suppressive effects of METTL1 overexpression on osteogenic differentiation and inflammatory responses.

CONCLUSIONS

These findings provide novel insights into the epigenetic regulation of periodontitis and suggest that targeting the METTL1-SEMA4D axis could offer a promising strategy for disease intervention.