Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis
Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis
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DOI：
10.1016/j.bbrc.2004.04.025
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发表时间：
2004-05-21
影响因子：
3.1
通讯作者：
Takayanagi, R
中科院分区：
文献类型：
--
作者：
Ohnaka, K;Taniguchi, H;Takayanagi, R
为了阐明糖皮质激素诱导骨质疏松症的潜在机制，我们研究了糖皮质激素对原代培养的人成骨细胞中 dickkopf-1 (Dkk-1)（Writ 信号传导拮抗剂）表达的影响。地塞米松以剂量和时间依赖性方式显着诱导 Dkk-1 mRNA 的表达。 Dkk 受体 Kremen] 的表达没有因地塞米松治疗而改变，而低密度脂蛋白受体相关蛋白 5（LRP5）（Writ 辅助受体）的表达因地塞米松治疗而略有下降。地塞米松增加了人成骨细胞中 Dkk-1 基因启动子的转录活性。 Dkk-1启动子的连续缺失和突变分析表明，位于-788至-774 bp的一个假定的糖皮质激素反应元件样序列对于地塞米松在人成骨细胞中增强Dkk-1启动子活性至关重要。由于Writ信号现在被认为是骨形成的关键调节因子，糖皮质激素增强的Dkk-1可能会抑制成骨细胞中的Writ信号，这可能参与糖皮质激素诱导的骨质疏松症的发病机制。 (C) 2004 Elsevier Inc. 保留所有权利。
To clarify the underlying mechanism of glucocorticoid-induced osteoporosis, we investigated the effect of glucocorticoid on the expression of dickkopf-1 (Dkk-1), an antagonist of Writ signaling, in primary cultured human osteoblasts. Dexamethasone markedly induced the expression of mRNA for Dkk-1 in a dose- and time-dependent manner. The expression of Kremen], a receptor for Dkk, did not change by the treatment with dexamethasone, while that of low-density lipoprotein receptor-related protein 5 (LRP5), a Writ coreceptor, slightly decreased by the treatment with dexamethasone. Dexamethasone increased the transcriptional activity of the Dkk-1 gene promoter in human osteoblasts. Serial deletion and mutation analyses of the Dkk-1 promoter showed that one putative glucocorticoid responsive element-like sequence located from -788 to -774 bp is essential for the enhancement of the Dkk-1 promoter activity by dexamethasone in human osteoblasts. Since the Writ signal is now recognized as a crucial regulator for bone formation, the Dkk-1 enhanced by glucocorticoid may inhibit the Writ signal in osteoblasts, which may be involved in the pathogenesis of glucocorticoid-induced osteoporosis. (C) 2004 Elsevier Inc. All rights reserved.