Kaempferol, Sodium Fluoride, Metformin, and Simvastatin: The Role of Autophagy in Oral Bone Tissue Regeneration

Kaempferol, a flavonoid compound, has been found to have a protective effect on oral bone tissue by inhibiting bisphosphonate-induced osteonecrosis in the mandible. It achieves this by up-regulating osteoclast apoptosis and down-regulating osteoclast formation [183]. Kaempferol has also been found to inhibit autophagy in osteoclasts by degrading p62/SQSTM1 and activating apoptosis in murine [183]. Additionally, it stimulates osteogenic differentiation by inducing autophagy in cultured osteoblasts [184]. Although the effects of kaempferol on autophagy vary depending on the cell types, they are both beneficial to oral bone tissue.

Sodium fluoride (NaF) is an essential chemical compound for tooth development and can modulate dental stem cell differentiation by manipulating autophagy [185]. One study found that NaF (0.5 mM) significantly enhanced the osteo/odontogenesis of stem cells from the apical papilla, and the expression of autophagy-related proteins in NaF-treated stem cells also increased. Silencing Atg5 to block autophagy decreased the expression of osteo/odontogenic markers [185].

Metformin has been found to relieve the accumulation of ROS induced by high concentrations of nano-biomaterial polydopamine-templated hydroxyapatite (tHA) by activating the AMPK/mTOR signaling pathway and autophagy. This results in the induction of osteogenesis in human PDLSCs [186]. In osteosarcoma cells, increased autophagy and TGF-β signaling pathway activation by leptin were associated with chemoresistance [187]. Additionally, there was a significant correlation between the level of autophagy in clinical osteosarcoma samples and patient prognosis.

Simvastatin, a small molecule drug, has been proven to improve and accelerate the osseointegration of implants in the oral cavity by activating autophagy and osteogenesis, and inhibiting osteoclast activity [188]. Simvastatin restores LC3-II levels in 3-MA-stimulated BMMSCs and further promotes LC3-II and Beclin1 expression while downregulating p62 expression in rapamycin-stimulated BMMSCs [188]. Moreover, simvastatin increases the mineral deposits of BMMSCs that are cultured in osteogenic media in the presence of 3-MA or rapamycin, suggesting that simvastatin increases osteogenic differentiation via the promotion of autophagy.