Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3.
Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3.
复制标题
Ro-26-9228（维生素 D3 的非钙血症类似物）对组织和细胞类型选择性激活维生素 D 受体的证据。
DOI：
10.1002/jcb.10344
复制
发表时间：
2003
影响因子：
4
通讯作者：
Avnur,Zafrira
中科院分区：
文献类型：
--
作者：
Peleg,Sara;Ismail,Ayesha;Uskokovic,MilanR;Avnur,Zafrira
我们最近的研究表明，维生素D类似物Ro-26 - 9228可恢复骨质疏松大鼠的骨密度，而不会诱导高钙血症。我们的体外实验表明，类似物上调基因表达的骨小梁，但不是在十二指肠的雌性大鼠。我们检查了Ro-26 - 9228在Caco-2（一种肠源性人细胞系）和hFOB以及人胎儿成骨细胞系中的组织选择性机制。我们发现Ro-26 - 9228和天然激素1，25-二羟维生素D3（1，25 D3）诱导瞬时转染的人成骨细胞中VDRE-报告基因表达的能力相似。相比之下，在Caco-2细胞中，Ro-26 - 9228诱导的报告基因表达比1，25 D3少40倍。我们还在下拉试验中检查了来自这两种细胞系的维生素D受体（VDR）-配体复合物与转录伴侣（糖皮质激素受体相互作用蛋白、VDR相互作用蛋白和类维生素A X受体）相互作用的能力。这些试验表明，1，25 D3诱导这些辅因子与成骨细胞和肠细胞中VDR的相互作用水平相似。相比之下，Ro-26 - 9228诱导成骨细胞的VDR与这些辅因子的显著相互作用，但诱导Caco-2细胞的VDR较少。这些结果表明，与成骨细胞不同，肠细胞的细胞环境抑制了VDR-Ro-26 - 9228复合物与转录伴侣相互作用的能力。J.细胞。88：267-273，2003.© 2002 Wiley利斯公司
Our recent studies have shown that the vitamin D analog Ro‐26‐9228 restores bone mineral density without inducing hypercalcemia in osteopenic rats. Our ex vivo experiments demonstrated that the analog upregulated gene expression in trabecular bone but not in the duodenum of female rats. We examined the mechanism for the tissue selectivity of Ro‐26‐9228 in Caco‐2, a human cell line of intestinal origin, and hFOB, and a human fetal osteoblast cell line. We found that the abilities of Ro‐26‐9228 and the natural hormone, 1,25‐dihydroxyvitamin D3(1,25D3) to induce VDRE‐reporter gene expression in transiently transfected human osteoblasts are similar. In contrast, in Caco‐2 cells, Ro‐26‐9228 induces 40‐fold less reporter gene expression than 1,25D3does. We also examined the abilities of the vitamin D receptor (VDR)‐ligand complexes from these two cell lines to interact with partners of transcription (glucocorticoid receptor‐interacting protein, VDR‐interacting protein, and retinoid X receptor), in pull‐down assays. These assays revealed that 1,25D3induces similar levels of interaction of these co‐factors with VDR from both osteoblasts and intestinal cells. In contrast, Ro‐26‐9228 induces significant interaction of VDR from osteoblast cells with these co‐factors, but less of VDR from Caco‐2 cells. These results suggest that the cellular environment of intestinal cells, unlike that of osteoblasts, represses the ability of VDR‐Ro‐26‐9228 complexes to interact with transcription partners. J. Cell. Biochem. 88: 267–273, 2003. © 2002 Wiley‐Liss, Inc.