Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2
Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2
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DOI：
10.1016/s0014-4827(03)00213-1
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发表时间：
2003-08-15
影响因子：
3.7
通讯作者：
Knecht, N
中科院分区：
文献类型：
--
作者：
Beck, GR;Moran, E;Knecht, N
成骨细胞分化和基质矿化的过程需要碱性磷酸酶活性的增加，从而产生游离磷。无机磷调节基因转录和细胞功能的能力代表了一种潜在的新的胞外信号机制。利用微阵列分析，我们已经确定了一组离散的基因，这些基因在MC3T3-E1细胞中受到磷酸盐增加的正向或负向调控。被磷酸盐下调的基因编码与成骨细胞相关的细胞外因子，如胶原蛋白、Periostin和核心蛋白。磷酸盐增加的基因编码一组新的转录因子，这些转录因子可能在成骨细胞发育的后期阶段发挥重要作用，在成骨细胞发育的环境中磷酸盐含量很高。转录因子Nrf2就是这样一个基因。升高的磷酸盐水平刺激Nrf2 RNA的增加，这不能被翻译抑制剂放线菌亚胺所阻断，这表明Nrf2是一个即时反应基因。克隆小鼠Nrf2启动子表明，升高的磷酸盐产生的启动子活性增加，这是时间和剂量依赖的。这一分析揭示了与成骨细胞分化相关的磷酸盐增加所调控的多个基因，加深了我们对成骨细胞与其细胞外环境之间错综复杂的交流的理解。(C)2003年埃尔塞维尔科学公司(美国)。版权所有。
The process of osteoblast differentiation and matrix mineralization requires a rise in alkaline phosphatase enzymatic activity resulting in the generation of free phosphate. The ability of inorganic phosphate to regulate gene transcription and cellular function represents a potentially novel extracellular signaling mechanism. Using microarray analysis we have identified a discrete set of genes that are either positively or negatively regulated by increased phosphate in MC3T3-E1 cells. The genes downregulated by phosphate encode for osteoblast-related extracellular factors such as collagens, periostin, and decorin. The genes increased by phosphate encode a novel group of transcription factors that may be important in the later stages of osteoblast development in which the environment is high in phosphate. The transcription factor Nrf2 is one such gene. Elevated phosphate levels stimulate an increase in Nrf2 RNA that is not blocked by the translation inhibitor cycloheximide, suggesting that Nrf2 is an immediate response gene. Cloning of the murine nrf2 promoter reveals that elevated phosphate produces an increase in promoter activity that is both time and dose dependent. This analysis reveals multiple genes regulated by the increase in phosphate associated with osteoblast differentiation, adding to our understanding of the intricate communication between osteoblasts and their extracellular environment. (C) 2003 Elsevier Science (USA). All rights reserved.