Disorder of vitamin D metabolism in steroid-induced osteoporosis

类固醇引起的骨质疏松症中维生素 D 代谢紊乱

• 批准号: 10470393
• 负责人: HORIUCHI Noboru
• 金额: $ 8.45万
• 依托单位: Ohu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470393/
• 关键词: Osteoporosis; Glucocorticoid; 1a-hydroxylase; 24-hydroxylase; Vitamin D receptor; Transcriptional regulation

Glucocorticoid osteoporosis is the most common cause of drug-relate osteoporosis. Recent in vivo experiment showed that administration of glucocorticoids such as dexamethasone into mice markedly increased vitamin D-24-hydroxylase mRNA abundance and the enzyme activity in kidney. However, the regulation of 24-hydroxylase expression by dexamethasone has not been known in the bone, a target tissue of glucocorticoids. This study was undertaken to define the regulatory mechanism of dexamethasone on 24-hydroxylase gene expression in osteoblasts. Dexamethasone in the presence of 10^<-7>M 1α, 25-Dihydroxyvitamin D_3 [1,25 (OH)_2D_3] stimulated the 24-hydroxylase mRNA abundance and enzyme activity by UMR-106 osteoblast-like cells in a dose- and time-dependent fashion. Dexamethasone stimulation of 24-hydroxylase mRNA expression in UMR-106 cells was abrogated completely by pretreatment with cycloheximide, an inhibitor of protein synthesis, indicating that new protein synthesis is required for this stimulation. Northern blot analysis revealed that 10^<-6>M dexamethasone in the presence of 10^<-7>M 1,25 (OH)_2D_3 markedly increased in a transcription factor, c-fos, mRNA abundance. Other steroid hormones including corticosterone, cortisol, aldosterone, testosterone, estrogen and progesterone could not enhance 24-hydroxylase mRNA expression in UMR-106 cells. These results indicated that dexamethasone stimulated the 24-hydroxylase gene expression mediated through c-fos induction in the presence of 1,25 (OH)_2D_3 in osteoblasts.

糖皮质激素性骨质疏松症是药物性骨质疏松症最常见的原因。最近的体内实验表明，给小鼠注射糖皮质激素（如地塞米松）可显著增加肾脏中维生素D-24-羟化酶mRNA的丰度和酶活性。然而，地塞米松对骨（糖皮质激素的靶组织）中24-羟化酶表达的调节尚不清楚。本研究旨在探讨地塞米松对成骨细胞24-羟化酶基因表达的调控机制。地塞米松在10 μ <-7>M 1α，25-二羟基维生素D_3 [1，25（OH）_2D_3]的存在下以剂量和时间依赖的方式刺激UMR-106成骨样细胞24-羟化酶mRNA丰度和酶活性。地塞米松刺激的24-羟化酶mRNA的表达在UMR-106细胞被废除完全预处理放线菌酮，蛋白质合成的抑制剂，表明新的蛋白质合成需要这种刺激。北方印迹分析显示，10 μ <-6>M地塞米松在10 μ <-7>M 1，25（OH）_2D_3存在下显著增加了转录因子c-fos mRNA的丰度。其他甾体激素如皮质酮、皮质醇、醛固酮、睾酮、雌激素和孕酮均不能促进UMR-106细胞24-羟化酶mRNA的表达。结果表明，地塞米松通过诱导c-fos基因表达，促进了1，25（OH）_2D_3诱导的成骨细胞24-羟化酶基因表达。

项目成果

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Setsuo Hamada：“中枢神经降钙素受体调节小肠运输。”激素和代谢研究。

Nagako Akeno: "Regulation of vitamin D-1α-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney."Journal of Endocrinology. 164(3). 339-348 (2000)

Nagako Akeno：“地塞米松对小鼠肾脏中维生素 D-1α-羟化酶和 -24-羟化酶表达的调节”。内分泌学杂志 164(3) 339-348 (2000)。

Tetsuya Kawane: "Insulin-like growth factor I suppresses parathyroid hormone (PTH)/PTH-related protein receptor expression via a mitogen-activated protein kinase pathway in UMR-106 osteoblast-like cells."Endocrinology. 140(2). 871-879 (1999)

Tetsuya Kawane：“胰岛素样生长因子 I 通过 UMR-106 成骨细胞样细胞中的丝裂原激活蛋白激酶途径抑制甲状旁腺激素 (PTH)/PTH 相关蛋白受体的表达。”内分泌学。

Nagako Akeno: "Mouse vitamin D-24-hydroxylase: molecular cloning,tissue distribution,and transcriptional regulation by 1α,25-dihydroxyvitamin D_3." Endocrinology. 138. 2233-2240 (1997)

Nagako Akeno：“小鼠维生素 D-24-羟化酶：1α,25-二羟基维生素 D_3 的分子克隆、组织分布和转录调节。”138. 2233-2240 (1997)

Toyonobu Maeda: "Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells."Biochemical and Biophysical Research Communications. 280(3). 874-877 (2001)

Toyonobu Maeda：“辛伐他汀促进 MC3T3-E1 细胞中的成骨细胞分化和矿化。”生物化学和生物物理研究通讯。