Osteoprotective Role of the Mir338 Cluster Ablation during Periodontitis

Periodontitis is a chronic inflammatory disease that compromises the integrity of the supporting tissues of the teeth and leads to the loss of the alveolar bone. The Mir338 cluster has been proven to be a potential target for the treatment of osteoporosis and is also enriched in gingival tissues with periodontitis; however, its role in periodontitis remains unknown. Here, we aimed to use periodontitis as a model to expand our understanding of the Mir338 cluster in osteoimmunology and propose a new target to protect against bone loss during periodontitis progression. Significant enrichment of the Mir338 cluster was validated in gingival tissues from patients with chronic periodontitis and a ligature-induced periodontitis mouse model. In vivo, attenuation of alveolar bone loss after 7 d of ligature was observed in the Mir338 cluster knockout (KO) mice. Interestingly, immunofluorescence and RNA sequencing showed that ablation of the Mir338 cluster reduced osteoclast formation and elevated the inflammatory response, with enrichment of IFN-γ and JAK-STAT signaling pathways. Ablation of the Mir338 cluster also skewed macrophages toward the M1 phenotype and inhibited osteoclastogenesis via Stat1 in vitro and in vivo. Furthermore, the local administration of miR-338-3p antagomir prevented alveolar bone loss from periodontitis. In conclusion, the Mir338 cluster balanced M1 macrophage polarization and osteoclastogenesis and could serve as a novel therapeutic target against periodontitis-related alveolar bone loss.