Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene (Retracted article. See vol. 34, pg. 918, 2014)
Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene (Retracted article. See vol. 34, pg. 918, 2014)
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DOI：
10.1128/mcb.00813-07
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发表时间：
2007-11-01
影响因子：
5.3
通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
--
作者：
Igarashi, Mamoru;Yogiashi, Yoshiko;Kato, Shigeaki
维生素 K 是一种脂溶性维生素，可作为维生素 K 依赖性羧化酶的辅酶。除了其典型作用外，维生素 K 还能与类固醇和异生物质受体 (SXR)/孕烷 X 受体 (PXR) 结合并调节基因转录。为了确定维生素 K 的骨保护作用是否是 PXR/SXR 途径的结果，我们通过二维十二烷基硫酸钠-聚丙烯酰胺凝胶电泳筛选了用维生素 K2（甲基萘醌 4 [MK4]）处理的成骨细胞系（MC3T3-E1）中的 PXR/SXR 靶基因。 MK4 诱导 MC3T3-E1 细胞的成骨细胞分化。 Msx2 是一种成骨细胞转录因子，被鉴定为 MK4 诱导基因。 Msx2 基因启动子的功能分析绘制了维生素 K 响应元件（PXR 响应元件 [PXRE]）的图谱，该元件直接与 PXR/类视黄醇 X 受体 α 异二聚体结合。在染色质免疫沉淀分析中，PXR 与共激活因子 p300 一起被募集至 Msx2 启动子中的 PXRE。 MK4 结合的 PXR 与雌激素结合的雌激素受体 a 协同控制 Msx2 启动子的转录。 PXR 或 Msx2 的敲低减弱了 MK4 对成骨细胞分化的影响。因此，本研究表明，Msx2 是维生素 K 激活的 PXR 的靶基因，并表明 MK4 在人体中的骨保护作用至少部分介导维生素 K 信号传导的基因组途径。
Vitamin K is a fat-soluble vitamin that serves as a coenzyme for vitamin K-dependent carboxylase. Besides its canonical action, vitamin K binds to the steroid and xenobiotic receptor (SXR)/pregnane X receptor (PXR) and modulates gene transcription. To determine if the osteoprotective action of vitamin K is the result of the PXR/SXR pathway, we screened by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis the PXR/SXR target genes in an osteoblastic cell line (MC3T3-E1) treated with a vitamin K2 (menaquinone 4 [MK4]). Osteoblastic differentiation of MC3T3-E1 cells was induced by MK4. Msx2, an osteoblastogenic transcription factor, was identified as an MK4-induced gene. Functional analysis of the Msx2 gene promoter mapped a vitamin K-responsive element (PXR-responsive element [PXRE]) that was directly bound by a PXR/retinoid X receptor alpha heterodimer. In a chromatin immunoprecipitation analysis, PXR was recruited together with a coactivator, p300, to the PXRE in the Msx2 promoter. MK4-bound PXR cooperated with estrogen-bound estrogen receptor a to control transcription at the Msx2 promoter. Knockdown of either PXR or Msx2 attenuated the effect of MK4 on osteoblastic differentiation. Thus, the present study suggests that Msx2 is a target gene for PXR activated by vitamin K and suggests that the osteoprotective action of MK4 in the human mediates, at least in part, a genomic pathway of vitamin K signaling.