Abstract
Fluorine may result in damage to teeth, bones and other body tissues, and is a serious public health problem. SIRT1 deacetylates FOXOs, which brings about apoptosis and autophagy promotion or suppression. Fluorine may induce cell apoptosis, however, the role of autophagy in apoptosis induced by fluorine is still poorly understood, and the interaction between SIRT1 and FOXOs should be further illustrated. Therefore, this study investigated the mechanisms underlying the NaF- induced apoptosis and autophagy in osteoblast-like MC3T3-E1 cells in vitro through activating or inhibiting SIRT1. Via RT-PCR, western blot, flow cytometry assays, fluorescence and laser confocal microscopy, it was found that NaF induced both cell apoptosis and autophagy. Results also showed that NaF up-regulated SIRT1 expression in a dose-dependent manner. The autophagy of MC3T3-E1 was also up- regulated indirectly whilst apoptosis was significantly attenuated when incubated with the SIRT1 activator SRT1720. When SIRT1 inhibitor Ex-527 was used, the latter effects were reversed. Furthermore, SIRT1 increased deacetylation of FoxO1 and promoted the up-regulation of its target substrate Rab7, as well as increase of Bnip3 which was substrate of FoxO3, and we hypothesize that these pathways may cause an increase in autophagic flux and a reduction in apoptosis. In conclusion, SIRT1-induced autophagy enhancement protects against fluoride-induced apoptosis through autophagy induction in MC3T3-E1 cells, which may be associated with a SIRT1-FoxO1-Rab7 axis and a SIRT1-FoxO3-Binp3 axis. The role of SIRT1 in selecting between cell survival and death provides a potential therapeutic strategy in fluorosis.
Highlights
Fluorine is indispensable for teeth and bones since it can prevent enamel and root caries, as well as stimulate the formation of bones
In this study we examined whether FOXOs participate in the effect of SIRT1 modulators in osteoblast-like MC3T3-E1 cells exposed to fluoride
We showed that NaF treatment led to significant apoptosis in MC3T3-E1 cells via caspase-3 activation, a feature that could be verified by Annexin V-FITC/PI staining
Summary
Fluorine is indispensable for teeth and bones since it can prevent enamel and root caries, as well as stimulate the formation of bones. Low levels of fluorine intake (0.8~1.2 mg/L) are beneficial being frequently included in toothpaste; high intake levels (> 1.5 mg/L) may induce pitting corrosion in enamel, a phenomenon called dental fluorosis. It can cause alterations in bone structure leading to conditions such as osteoporosis and osteosclerosis. Fluorine is critical for protecting teeth and bones, and on the other hand, excess fluorine can result in damage to both along with other body tissues. Fluorosis remains a public health challenge world-wide, and there are endemic fluorosis districts in most areas in China [1]
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