N6-Methyladenosine (m6A) RNA Modification in Periodontitis: Molecular Mechanisms and Therapeutic Potential: A Narrative Review

Abstract

Background: N6-methyladenosine (m6A) is the most abundant mRNA internal modification in eukaryotes and regulates inflammatory and regenerative processes. Many studies relate the dysregulation of m6A-related pathways to periodontal inflammation, imbalance in cell homeostasis, impaired tissue regeneration, and remodeling of the alveolar bone. However, the mechanisms of the relationship between the m6A pathway and periodontitis have not been elucidated clearly yet. Objective: The objective of the current narrative review is to integrate the information related to the role of m6A RNA modification in the pathogenesis of periodontitis by focusing on inflammatory signaling, osteoimmune regulation, periodontal cell activity, bone remodeling, and its possible applications as a diagnosis and treatment approach. Methods: A literature search was conducted in PubMed to identify original research studies investigating the role of m6A RNA methylation and its regulators in periodontitis and periodontal tissues/cells. Out of 49 publications reviewed, 34 original research articles fulfilled the predetermined inclusion criteria. Results: The current literature suggests that N6-methyladenosine (m6A) modification is involved in various interconnected biological processes contributing to the development of periodontitis, including inflammatory responses, inflammasome activation and pyroptosis, osteoimmune reactions by macrophages, osteogenic differentiation, osteoclast formation, cellular senescence, and periodontal cells homeostasis. METTL3 has been reported to be the most widely investigated regulator, but its roles are not consistently harmful or beneficial. Depending on the RNA target, cellular environment, and state of inflammation, some of the m6A-associated pathways have been linked to periodontal inflammation and alveolar bone resorption, while others were linked to osteogenesis and regeneration. Several studies have highlighted the possibility of therapeutic interference in pathways leading to the formation of m6A, while human transcriptomic and gingival/salivary studies suggested that m6A could be used as a biomarker. Conclusions: The m6A modification of RNA is an emerging epitranscriptomic effect relating periodontal inflammation, immune responses, cellular differentiation, and bone remodeling. Even though target molecules and signaling pathways have been experimentally identified as points of potential therapeutic interference, the available evidence remains predominantly preclinical. Future work is expected to validate the diagnostic and therapeutic involvement of the m6A modification in periodontitis.