Glutamate is a determinant of cellular proliferation through modulation of nuclear factor E2 p45‐related factor‐2 expression in osteoblastic MC3T3‐E1 cells
Glutamate is a determinant of cellular proliferation through modulation of nuclear factor E2 p45‐related factor‐2 expression in osteoblastic MC3T3‐E1 cells
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DOI：
10.1002/jcp.21095
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发表时间：
2007-10
影响因子：
5.6
通讯作者：
K. Uno;T. Takarada;E. Hinoi;Y. Yoneda
中科院分区：
文献类型：
--
作者：
K. Uno;T. Takarada;E. Hinoi;Y. Yoneda
特定谷氨酸（Glu）受体的激活显示在成骨细胞生成期间促进细胞向成熟分化。在本研究中，我们评估了Glu对成骨细胞增殖的可能调节，这些细胞具有增殖自我更新和向成熟成骨细胞分化的能力。在分化前，暴露于浓度超过500 µM的Glu显著抑制成骨细胞MC 3 T3-E1的增殖活性，而不诱导细胞死亡。Glu的抑制作用对胱氨酸或还原型谷胱甘肽的抑制作用敏感。在这些未分化成骨细胞中首次显示了由xCT和4F 2 hc亚基组成的胱氨酸/Glu反向转运蛋白的mRNA表达。在用Glu培养的未分化MC 3 T3-E1细胞中观察到细胞内总谷胱甘肽水平显著降低，而分别添加谷胱甘肽耗尽剂环己烯-1-酮和谷胱甘肽生物合成抑制剂L-丁硫氨酸-[S，R]-亚砜亚胺则显著降低了细胞增殖活性。暴露于Glu导致核因子E2 p45相关因子2（Nrf 2）的mRNA表达显著增加，同时产生活性氧，而在Nrf 2稳定过表达的MC 3 T3-E1细胞中观察到增殖活性显著降低。这些结果表明，Glu可以通过与Nrf 2表达上调相关的机制抑制细胞增殖，该机制与促进未分化MC 3 T3-E1细胞中胱氨酸/Glu反向转运蛋白的逆行操作后细胞内谷胱甘肽的消耗相关。J.细胞。213：105-114，2007。© 2007 Wiley利斯公司
Activation of particular glutamate (Glu) receptors is shown to promote cellular differentiation toward maturation during osteoblastogenesis. In the present study, we have evaluated the possible modulation by Glu of cellular proliferation in osteoblastic cells endowed to proliferate for self‐renewal and to differentiate toward matured osteoblasts. Exposure to Glu significantly suppressed the proliferation activity at a concentration over 500 µM without inducing cell death in osteoblastic MC3T3‐E1 cells before differentiation. The suppression by Glu occurred in a manner sensitive to the prevention by either cystine or reduced glutathione. Expression of mRNA was for the first time shown with the cystine/Glu antiporter composed of xCT and 4F2hc subunits in these undifferentiated osteoblastic cells. A significant decrease was seen in intracellular total glutathione levels in undifferentiated MC3T3‐E1 cells cultured with Glu, indeed, whereas the cellular proliferation activity was drastically decreased by the addition of the glutathione depleter cyclohexene‐1‐one and the glutathione biosynthesis inhibitor L‐buthionine‐[S,R]‐sulfoximine, respectively. Exposure to Glu led to a significant increase in mRNA expression of nuclear factor E2 p45‐related factor 2 (Nrf2) together with the generation of reactive oxygen species, while a significant decrease was seen in the proliferation activity in MC3T3‐E1 cells with stable overexpression of Nrf2. These results suggest that Glu could suppress the cellular proliferation toward self‐renewal through a mechanism associated with the upregulation of Nrf2 expression in association with the depletion of intracellular glutathione after promoting the retrograde operation of the cystine/Glu antiporter in undifferentiated MC3T3‐E1 cells. J. Cell. Physiol. 213: 105–114, 2007. © 2007 Wiley‐Liss, Inc.