Argpyrimidine bonded to RAGE regulates autophagy and cell cycle to cause periodontal destruction

Abstract

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 APMDinduced 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, proinflammatory 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.

The role of autophagy in odontogenesis, dental implant surgery, periapical and periodontal diseases

“…76 Argpyrimidine, one of the main products of diabetes, has been implicated in autophagy of PDLCs via PI3K/AKT/mTOR. 77 High glucose hindered the activity of PLSC in diabetic rat models, but the modulation of autophagy helped maintain cell function. Modulating autophagy somewhat counteracted the adverse impact of high glucose circumstances on PLSC.…”

“…Diabetic rats have shown an intense inflammatory response and reduced autophagy compared with non‐diabetic rats 76 . Argpyrimidine, one of the main products of diabetes, has been implicated in autophagy of PDLCs via PI3K/AKT/mTOR 77 . High glucose hindered the activity of PLSC in diabetic rat models, but the modulation of autophagy helped maintain cell function.…”

mTOR Signaling Pathway in Bone Diseases Associated with Hyperglycemia

“…Besides, excessive ERS caused by glutathione peroxidase 7 (GPx7) knockdown negatively regulated AKT/mTOR activity and inhibited osteogenic differentiation of BMSCs [71]. Similarly, arginine pyrimidine (APMD), a core product of DM, downregulated the PI3K/AKT/mTOR pathway in periodontal cells and activated autophagy, thus promoting periodontal bone destruction [72].…”