Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts
Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts
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DOI：
10.1210/me.2003-0247
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发表时间：
2004-06-01
影响因子：
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通讯作者：
Aarnisalo, P
中科院分区：
文献类型：
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作者：
Lammi, J;Huppunen, J;Aarnisalo, P
孤儿核受体Nurr1主要在中枢神经系统中表达，但在某些外周组织如骨中也能检测到。为了阐明Nurr1在骨中的作用，我们检测了Nurr1在成骨细胞系中调节骨桥蛋白（OPN）表达的能力。在成骨细胞中转染Nurr1可增加OPN mRNA的表达。一个显性的Nurr1阴性变体消除了PTH诱导OPN表达的能力，这表明Nurr1参与了PTH介导OPN的调节。Nurr1有效地激活了由小鼠OPN启动子的-857/+191片段驱动的荧光素酶报告结构。OPN启动子的激活是由Nurr1的单体形式介导的，需要Nurr1直接结合到OPN启动子上，并且依赖于氨基末端的转激活功能-1。OPN启动子也受维生素D受体和雌激素相关受体的调控。我们发现Nurr1和维生素D以协同方式激活OPN启动子，而Nurr1介导的OPN启动子的转激活受到雌激素相关受体的抑制。综上所述，Nurr1在成骨细胞中直接激活OPN启动子，提示Nurr1在骨稳态调节中发挥作用。
The orphan nuclear receptor Nurr1 is mainly expressed in the central nervous system but is also detected in certain peripheral tissues such as bone. To elucidate the role of Nurr1 in bone, we examined the ability of Nurr1 to regulate osteopontin (OPN) expression in osteoblastic cell lines. Transfection of Nurr1 in osteoblastic cells increased OPN mRNA expression. A dominant negative Nurr1 variant abolished the ability of PTH to induce OPN expression, suggesting that Nurr1 is involved in mediating the regulation of OPN by PTH. Nurr1 efficiently transactivated a luciferase reporter construct driven by the -857/+191 fragment of the mouse OPN promoter. The activation of the OPN promoter was mediated by the monomeric form of Nurr1, required direct binding of Nurr1 to the OPN promoter, and was dependent on the amino-terminal transactivation function-1. The OPN promoter is also regulated by vitamin D receptor and estrogen-related receptors. We show that Nurr1 and vitamin D activate the OPN promoter in a synergistic fashion, whereas Nurr1-mediated transactivation of the OPN promoter is repressed by estrogen-related receptors. In conclusion, Nurr1 activates the OPN promoter directly in osteoblastic cells, suggesting a role for Nurr1 in the regulation of bone homeostasis.