Disorder of vitamin D metabolism in steroid-induced osteoporosis

糖皮质激素骨质疏松症是药物相关性骨质疏松症的最常见原因。最近的体内实验表明，地塞米松等糖皮质激素可显著提高小鼠肾脏维生素d -24羟化酶mRNA丰度和酶活性。然而，地塞米松对骨中24-羟化酶表达的调节尚不清楚，骨是糖皮质激素的靶组织。本研究旨在明确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^<-7>M 1α， 25-二羟维生素D_3 [1,25 (OH)_2D_3]的作用下刺激UMR-106成骨样细胞的24-羟化酶mRNA丰度和酶活性呈剂量和时间依赖性。地塞米松对UMR-106细胞24-羟化酶mRNA表达的刺激作用被环己亚胺预处理完全消除，环己亚胺是一种蛋白质合成抑制剂，表明这种刺激需要新的蛋白质合成。Northern blot分析显示，10^<-7> m125 (OH)_2D_3存在时，10^<-7>M地塞米松显著增加转录因子c-fos mRNA丰度。其他类固醇激素包括皮质酮、皮质醇、醛固酮、睾酮、雌激素和孕酮均不能增强UMR-106细胞中24-羟化酶mRNA的表达。这些结果表明，地塞米松刺激成骨细胞在1,25 (OH)_2D_3存在下通过c-fos诱导介导的24-羟化酶基因表达。

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.