Armbrecht H J, Hodam T L, Boltz M A, Partridge N C, Brown A J, Kumar V B
Geriatric Research, Education and Clinical Center, St. Louis VA Medical Center, Missouri 63125, USA.
Endocrinology. 1998 Aug;139(8):3375-81. doi: 10.1210/endo.139.8.6134.
The expression of the vitamin D 24-hydroxylase is highly regulated in target tissues for 1,25-dihydroxyvitamin D3 (1,25(OH)2D), where it may modulate the action of 1,25(OH)2D. In UMR106 osteoblastic cells, 1,25(OH)2D and PTH synergistically induce 24-hydroxylase expression. The purpose of these studies was to characterize the interaction between 1,25(OH)2D and PTH with regard to the messenger RNA (mRNA) levels of the cytochrome P450 component of the 24-hydroxylase (CYP24). PTH alone had no effect on CYP24 mRNA levels, and 1,25(OH)2D alone produced only a modest increase. However, 1,25(OH)2D and PTH together synergistically increased CYP24 mRNA levels 3-fold compared with 1,25(OH)2D alone. PTH also increased the sensitivity of UMR cells to 1,25(OH)2D from 10(-8) to 10(-10) M. PTH worked through the cAMP signaling pathway as evidenced by the lack of effect of PTH (3-34) and by the full activity of 8-bromo-cAMP. PTH in the presence of 1,25(OH)2D increased CYP24 gene transcription as shown by nuclear run-on studies and by activation of a CYP24 promoter-reporter construct after transfection. PTH also increased vitamin D receptor number in UMR cells, but this occurred at times later than the increase in transcription. These studies demonstrate that PTH in the presence of 1,25(OH)2D works through the cAMP-dependent signaling pathway to increase transcription of the CYP24 gene, to increase CYP24 protein levels, and to increase 24-hydroxylase activity.
维生素D 24-羟化酶的表达在1,25-二羟维生素D3（1,25(OH)2D）的靶组织中受到高度调控，在这些组织中它可能调节1,25(OH)2D的作用。在UMR106成骨细胞中，1,25(OH)2D和甲状旁腺激素（PTH）协同诱导24-羟化酶表达。这些研究的目的是就24-羟化酶（CYP24）细胞色素P450成分的信使核糖核酸（mRNA）水平，来描述1,25(OH)2D与PTH之间的相互作用。单独的PTH对CYP24 mRNA水平没有影响，单独的1,25(OH)2D仅产生适度增加。然而，与单独使用1,25(OH)2D相比，1,25(OH)2D和PTH共同作用可使CYP24 mRNA水平协同增加3倍。PTH还将UMR细胞对1,25(OH)2D的敏感性从10^(-8) M提高到10^(-10) M。PTH通过环磷酸腺苷（cAMP）信号通路起作用，这一点可由PTH（3-34）缺乏效应以及8-溴-cAMP的完全活性来证明。如核转录实验所示以及转染后CYP24启动子-报告基因构建体的激活所表明的，在1,25(OH)2D存在的情况下，PTH增加了CYP24基因转录。PTH还增加了UMR细胞中维生素D受体的数量，但这发生的时间比转录增加的时间要晚。这些研究表明，在1,25(OH)2D存在的情况下，PTH通过cAMP依赖性信号通路起作用，以增加CYP24基因的转录，提高CYP24蛋白水平，并增加24-羟化酶活性。
