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维生素D受体调节对成骨样细胞中1,25 - 二羟基维生素D3诱导的24 - 羟化酶活性的影响:C24 - 氧化途径的启动

Consequences of vitamin D receptor regulation for the 1,25-dihydroxyvitamin D3-induced 24-hydroxylase activity in osteoblast-like cells: initiation of the C24-oxidation pathway.

作者信息

Staal A, van den Bemd G J, Birkenhäger J C, Pols H A, van Leeuwen J P

机构信息

Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.

出版信息

Bone. 1997 Mar;20(3):237-43. doi: 10.1016/s8756-3282(96)00371-7.

Abstract

A direct relationship between vitamin D receptor (VDR) level and target cell responsiveness to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown in osteoblast-like cell lines. However, we previously found an inverse relationship between the TGF beta-induced VDR up-regulation and subsequent 1,25-(OH)2D3-induced biological responses. A clear inhibition of the 1,25-(OH)2D3-induced stimulation of osteocalcin and osteopontin expression was observed. A biological response that has formerly been shown to be coupled to VDR level is 24-hydroxylase activity. This enzyme initiates the C24 oxidation of the side-chain, followed by cleavage and ultimate metabolic clearance of both 25-(OH)D3 and its metabolite 1,25-(OH)2D3. With UMR 106 (rat) and MG 63 (human) osteoblast-like cells, we show that after preincubation with TGF beta, which causes an increase in VDR level, 1,25-(OH)2D3 induction of 24-hydroxylase activity is also stimulated. In addition, we provide evidence that variations in VDR level induced by other means (PTH, EGF, medium change) are also closely associated with 1,25-(OH)2D3-induced 24-hydroxylase activity. Furthermore, we show that in MG 63 cells, but not in UMR 106 cells, TGF beta itself was able to increase the activity of the enzyme 24-hydroxylase. As 24-hydroxylation is the initial step in the further C24 oxidation of 1,25-(OH)2D3, our results indicate a close coupling of VDR level and the degradation of its ligand, 1,25-(OH)2D3. This mechanism may provide an important regulatory feedback in the action of 1,25-(OH)2D3 at target tissue/cell level.

摘要

在成骨细胞样细胞系中,已证实维生素D受体(VDR)水平与靶细胞对1,25 - 二羟维生素D3(1,25-(OH)2D3)的反应性之间存在直接关系。然而,我们之前发现转化生长因子β(TGFβ)诱导的VDR上调与随后1,25-(OH)2D3诱导的生物学反应之间存在负相关关系。观察到1,25-(OH)2D3诱导的骨钙素和骨桥蛋白表达明显受到抑制。一种先前已被证明与VDR水平相关的生物学反应是24 - 羟化酶活性。该酶启动侧链的C24氧化,随后25-(OH)D3及其代谢物1,25-(OH)2D3发生裂解并最终代谢清除。利用UMR 106(大鼠)和成骨样细胞MG 63(人),我们发现,在用TGFβ预孵育导致VDR水平升高后,1,25-(OH)2D3诱导的24 - 羟化酶活性也受到刺激。此外,我们提供证据表明,由其他方式(甲状旁腺激素、表皮生长因子、更换培养基)诱导的VDR水平变化也与1,25-(OH)2D3诱导的24 - 羟化酶活性密切相关。此外,我们发现,在MG 63细胞中,但不在UMR 106细胞中,TGFβ本身能够增加24 - 羟化酶的活性。由于24 - 羟化是1,25-(OH)2D3进一步C24氧化的起始步骤,我们的结果表明VDR水平与其配体1,25-(OH)2D3的降解密切相关。该机制可能在靶组织/细胞水平上为1,25-(OH)2D3的作用提供重要的调节反馈。

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