Fluoride-induced c-Fos expression in MC3T3-E1 osteoblastic cells
Fluoride-induced c-Fos expression in MC3T3-E1 osteoblastic cells
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DOI：
10.3109/15376516.2015.1129570
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发表时间：
2016-02-12
影响因子：
3.2
通讯作者：
Matsuoka, Masato
中科院分区：
文献类型：
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作者：
Iwatsuki, Mamiko;Matsuoka, Masato
过量的氟全身暴露导致骨稳态紊乱。已知c-Fos通过影响成骨细胞和破骨细胞分化在骨发育中是必需的。本研究旨在探讨氟暴露对小鼠成骨细胞系MC 3 T3-E1中c-Fos表达及其调控信号通路的影响。氟化钠（NaF）可使MC 3 T3-E1细胞c-fos mRNA水平、c-Fos蛋白水平和c-Fos DNA结合活性显著升高，并在2或4 h达高峰。Fos家族的另一成员Fra-1蛋白也升高，而FosB和Fra-2蛋白保持不变。NaF进一步诱导促分裂原活化蛋白激酶（MAPK）的磷酸化，包括细胞外信号调节蛋白激酶1/2（ERK 1/2）、ERK 5、c-Jun NH 2-末端激酶和p38。NaF诱导的c-Fos蛋白表达被活化和非活化形式的MAPK/ERK激酶1/2（MEK 1/2）抑制剂U 0126和MEK 5抑制剂BIX 02189显著抑制，但被JNK抑制剂SP 600125和p38抑制剂SB 203580部分抑制。因此，ERK 1/2和ERK 5信号传导途径对于c-Fos的积累非常重要。针对小鼠c-fos基因的siRNA进一步增强NaF诱导的破骨细胞生成抑制剂OPG的上调，表明c-Fos可能负调节成骨细胞中氟诱导的OPG表达。
Excessive systemic exposure to fluoride leads to disturbances of bone homeostasis. c-Fos is known to be essential in bone development by affecting osteoblast and osteoclast differentiation. In this study, we examined the effects of fluoride exposure on c-Fos expression and its regulatory signaling pathways in MC3T3-E1 mouse osteoblast cell line. c-fos mRNA level, c-Fos protein level and c-Fos DNA-binding activity were markedly increased, with a peak at 2 or 4h, in MC3T3-E1 cells exposed to sodium fluoride (NaF). Fra-1 protein, another member of Fos family, was also elevated, whereas FosB and Fra-2 proteins remained unchanged. NaF further induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase 1/2 (ERK1/2), ERK5, c-Jun NH2-terminal kinase and p38. NaF-induced expression of c-Fos protein was markedly suppressed with U0126, the inhibitor of both activated and non-activated forms of MAPK/ERK kinase 1/2 (MEK1/2) and BIX02189, the MEK5 inhibitor, but partially with SP600125, the JNK inhibitor and SB203580, the p38 inhibitor. Therefore, ERK1/2 and ERK5 signal transduction pathways are important for accumulating c-Fos. siRNA targeting against the mouse c-fos gene further enhanced NaF-induced up-regulation of osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, suggesting that c-Fos might negatively regulate OPG expression induced by fluoride in osteoblastic cells.