Argpyrimidine (APMD), a methylglyoxal-arginine-derived product, is one of the main products of diabetes mellitus. We aimed to systematically investigate the role of APMD in regulating autophagy activity, with a specific focus on the finding of APDM binding molecule, matching amino acid residues, autophagy flux and proteins, cell cycle arrest, cell skeleton and migration, PI3K/AKT/mTOR pathways, inflammatory signals, alveolar bone destruction, and inhibition verification. In this study, binding to 59/94/121 amino acid residues of advanced glycosylation end product receptor (RAGE), APMD suppressed PI3K/AKT/mTOR pathway to attenuate cell survival of periodontal ligament cells (PDLCs). Simultaneously, autophagy proteins ATG5, Beclin1, and LC3-II/I expression ratio were upregulated while P62/SQSTM was downregulated. Cell cycle arrested at G0/G1 with enhancing Cyclin D1/CDK4 and decreasing Cyclin A/CDK2 expression. Inhibition of autophagy abrogated APMD-induced cell cycle arrest. Furthermore, the inflammation regulation network of matrix metalloproteinase (MMP)-2, MMP-9, MAPKs and NF-κB pathways were activated by APMD. Rat periodontal models confirmed that APMD induced alveolar bone resorption, increased inflammatory infiltrates, and degraded collagen fibers through RAGE and PI3K. APMD-induced autophagy, G0/G1 arrest, pro-inflammatory signals activating and periodontal destruction were reversed by RAGE knockdown while aggravated by PI3K inhibitor. This study provides the first evidence that APMD bind to RAGE to regulate autophagy and cell cycle of PDLCs through the PI3K/AKT/mTOR pathway, thereby promoting periodontal destruction.
Keywords: PI3K/AKT/mTOR signaling pathway; RAGE; argpyrimidine; autophagy; cell cycle arrest.
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