Autophagy may protect MC3T3-E1 cells from fluoride-induced apoptosis

Wei, Min; Duan, Dongmei; Liu, Yujie; Wang, Zhigang; Li, Zhongli

doi:10.3892/mmr.2014.2079

Cited by 22 publications

(15 citation statements)

References 28 publications

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“…This result is consistent with current related studies in osteoblasts 38, 39. Many factors can affect both the autophagy and apoptosis of osteoblasts, including fluoride, high glucose, and paxilitaxel 40-42. However, the effect of DMT1 on the apoptosis and autophagy of osteoblasts is first reported here.…”

Section: Discussionsupporting

confidence: 93%

Regulation of DMT1 on autophagy and apoptosis in osteoblast

Liu¹,

Zhang²,

Meng³

et al. 2017

Int. J. Med. Sci.

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Iron overload has recently been associated with the changes in the bone microstructure that occur in osteoporosis. However, the effect of iron overload on osteoblasts is unclear. The purpose of this study was to explore the function of divalent metal transporter 1 (DMT1) in the pathological processes of osteoporosis. Osteoblast hFOB1.19 cells were cultured in medium supplemented with different concentrations (0, 50, 100, 200, 300, 400, 500 μmol/L) of ferric ammonium citrate (FAC) as a donor of ferric ions. We used western blotting and immunofluorescence to determine the levels of DMT1 after treatment with FAC. Apoptosis was evaluated by detecting the levels of cleaved caspase 3, BCL2, and BAX with western blotting. Autophagy was evaluated by detecting the levels of LC3 with western blotting and immunofluorescence. Beclin-1 expression was also assessed with western blotting. The autophagy inhibitor 3-methyladenine was used to determine whether autophagy affects the apoptosis induced by FAC. Our results show that FAC increased the levels of DMT1, upregulated the expression of BCL2, and downregulated the apoptosis-related proteins cleaved caspase 3 and BAX. Both LC3I/LC3II levels and beclin-1 were also increased, indicating that FAC increases the accumulation of autophagosomes in hFOB1.19 cells. FAC-induced autophagy was increased by the apoptosis inhibitor 3-MA but was reduced in DMT1 shRNA hFOB1.19 cells. These results suggest that the increased expression of DMT1 induces iron overload and iron overload induces osteoblast autophagy and apoptosis, thus affecting the pathological processes of osteoporosis. Clarifying the mechanisms underlying the effects of DMT1 will allow the identification of novel targets for the prevention and treatment of osteoporosis.

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Section: Discussionsupporting

confidence: 93%

Regulation of DMT1 on autophagy and apoptosis in osteoblast

Liu¹,

Zhang²,

Meng³

et al. 2017

Int. J. Med. Sci.

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“…Previous investigations have shown that fluoride induces autophagy in the LS8 ameloblast cell line and in MC3T3-E1 osteoblastic cells [Suzuki and Bartlett, 2014;Wei et al, 2014]. However, few studies have investigated whether fluoride induces autophagy in the rat ameloblast cell line HAT-7.…”

Section: Discussionmentioning

confidence: 99%

“…The functional relationship between autophagy and apoptosis is complex under certain circumstances. Autophagy may play a protective role in fluoride-induced apoptosis [Wei et al, 2014]. However, Mizushima et al [2008] found that excessive autophagy damaged a large number of proteins and intracellular organelles, finally causing cell death.…”

Section: Discussionmentioning

confidence: 99%

Effects of Fluoride on the Expression of Beclin1 and mTOR in Ameloblasts

Lei

Zhang²,

Kaiqiang³

et al. 2014

Cells Tissues Organs

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Exposure to high levels of fluoride (F^-) can result in dental fluorosis in different individuals, but the mechanism of dental fluorosis remains unclear. Autophagy is a highly conserved intracellular digestion process that degrades damaged organelles and protein aggregates. This study examined the effect of sodium fluoride (NaF) on the expression of Beclin1 and mTOR to elucidate the development mechanisms of dental fluorosis. HAT-7 cells were incubated with various concentrations of NaF, and autophagic vacuoles were studied by transmission electron microscopy. At both mRNA and protein level, expression of Beclin1, which is required for autophagosome formation and decreases the expression of mTOR, an autophagy-related complex, was increased at 1.2 mmol/l NaF compared to baseline (0 mmol/l NaF). Additionally, immunohistochemical analysis was performed on paraffin-embedded rat incisor sections to identify the expression of Beclin1 and mTOR proteins in vitro. Highly significant differences were detected compared to controls. In summary, our results demonstrate unequivocally that excessive amounts of fluoride cause autophagy of HAT-7 cells, indicating that autophagy is involved in dental fluorosis.

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“…It has also been postulated that the regulation of p62 is responsible for controlling the formation of intracellular inclusion bodies in autophagy, and Beclin1 is involved in the initial steps of the formation of autophagosomes. Recently, it was demonstrated that uoride also induces autophagy due to an increased expression of Beclin1 and LC3 and a decreased expression of p62 in osteoblasts [17,45]. Similarly, a dose-response pattern in LC3-II protein expression in ameloblastderived cells has been observed with uoride treatment [30], which decreases after increasing the concentration of uoride.…”

Section: Discussionmentioning

confidence: 92%

“…Autophagy is a quintessential component of a multitude of cellular and tissue metabolic events [16] and it has also been considered as a key component of tissue protective mechanisms against the detrimental effects of extrinsic factors [17]. Autophagy-related 5 (ATG5), Beclin1, LC3 and p62 play pivotal roles in the autophagy pathway.…”

Section: Introductionmentioning

confidence: 99%

Oral toxicity to high level sodium fluoride causes impairment of autophagy

Oka

Zhang

et al. 2020

Preprint

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Background: Gingival recession and concomitant alveolar bone resorption are hallmarks of periodontal diseases and excessive fluoride intake has some deleterious effects on teeth, bone and soft tissues. Autophagy is a highly conserved intracellular digestion process that degrades damaged proteins and organelles but the biological roles of autophagy in pathological aspects of oral tissues remain largely unknown. We sought to elucidate the function of autophagy, especially its interplay with apoptosis and oxidative stress, in the oral toxicity induced by exposure to 5 mM sodium fluoride (NaF). Methods: HCEM2 cementoblast cells in culture were exposed to 5 mM NaF for 5 min, after which cell viability and cell apoptosis were assessed using the MTS assay and an Annexin V-FITC/PI apoptosis detection kit, respectively. Real-time quantitative RT-PCR and Western blotting were performed to characterize the mRNA and protein expression levels of markers for autophagy, apoptosis, and oxidative stress. C57BL/6 mice were exposed to 5 mM NaF in their drinking water from 12 to 58 weeks. Micro-computed tomography was used to measure changes in their alveolar bone while immunohistochemistry and immunofluorescence staining was used to evaluate protein expression levels of autophagy, apoptosis, and oxidative stress markers.Results: Cementoblasts exposed to 5 mM NaF had decreased levels of autophagy, as shown by reduced expression levels of ATG5, Beclin1 and LC3-II, elicited excessive apoptosis, which in turn induced oxidative stress and inflammation, as manifested by elevated levels of Bax, cleaved caspase-3, SOD1 and phospho NF-κB. Consistently, the in vivo results verified the findings of the in vitro study and treatment of mice with 5 mM NaF resulted in histological abnormalities in periodontal tissues, induced excessive oxidative stress and apoptosis, and reduced autophagy. These results correlated with the immunofluorescence observations, thus confirming the pivotal role of autophagic flux dysfunction in 5 mM NaF-induced cell death. Micro-computed tomography analysis demonstrated that 5 mM NaF caused a decrease in bone areas of mice compared with controls. Exposure to 5 mM NaF induced RANKL (receptor activator of nuclear factor κB ligand) and cathepsin K expression in periodontal tissues, while ATG5 and Beclin1 expression was abrogated by 5 mM NaF.Conclusion: Taken together, our findings suggest that 5 mM NaF elicits oral toxicity that contributes to excessive apoptosis, oxidative stress, and defective autophagy, which aggravates periodontal tissue damage.

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Autophagy may protect MC3T3-E1 cells from fluoride-induced apoptosis

Cited by 22 publications

References 28 publications

Regulation of DMT1 on autophagy and apoptosis in osteoblast

Regulation of DMT1 on autophagy and apoptosis in osteoblast

Effects of Fluoride on the Expression of Beclin1 and mTOR in Ameloblasts

Oral toxicity to high level sodium fluoride causes impairment of autophagy

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