Autophagy and Its Role in Periodontal Tissue Regeneration: A Review

A study conducted by An et al. [81] found that periodontal ligament (PDL) tissues from periodontitis patients exhibited higher expression of LC3 and autophagosomes. Activated autophagy protected PDLSCs against apoptosis in the inflammatory microenvironment of periodontitis. Additionally, TNF-α, an inflammatory cytokine, promoted autophagy in the early stages, but blocked it in the later stages after prolonged treatment in inflammatory-PDLSCs [81]. A20, also known as TNF-α-induced protein 3 (TNFAIP3), has an anti-inflammatory effect. Yan et al. [82] discovered that A20 positively contributes to periodontal tissue regeneration by inhibiting osteoclastogenesis via TRAF6-dependent autophagy up-regulation in hypoxia-treated human PDLCs. Moreover, another study reported that STAT3 inhibition decreased TNF-α-induced autophagy in cementoblasts [83]. However, Liu et al. revealed that in an inflammatory microenvironment mimicked by human gingival fibroblasts treated with P.g-derived LPS, the PI3K/Akt/mTOR pathway was inhibited, and autophagy levels were upregulated. Suppressing mTOR induced autophagy upregulation and decreased LPS-induced pro-inflammatory cytokine secretion, while autophagy inhibition had the opposite effect [84]. These results reflect the interplay between autophagy and cytokine secretion.

Senescent PDLSCs exhibit impaired regenerative potential, which hinders the outcomes of periodontal tissue regeneration. Enhancing autophagy can prevent cell senescence and peroxidation damage, thus facilitating periodontal tissue regeneration [33],[85]. According to Kuang’s study [33], PDLSCs pre-treated with metformin could down-regulate ROS accumulation, oxidative damage, lysosomal β-galactosidase activity, senescence-related gene expression, and up-regulate osteogenic differentiation, while autophagy inhibition by 3-MA abolished these effects under oxidative stress. Another study revealed that enhancing autophagy with melatonin protected long-term ex vivo expanded PDLSCs from cell senescence [85].