Role of Vitamin D hydroxylase on Bone Metabolism.

维生素 D 羟化酶对骨代谢的作用。

• 批准号: 12470392
• 负责人: SHINKI Toshimasa
• 金额: $ 9.41万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470392/
• 关键词: 1α,25-dihydroxyvitamin D_3; 24,25-dihydroxyvitamin D_3; megalin; transgenic rat; 25-hydroxyvitamin D_3; kidney; vitamin D binding protein; glomerulosclerosis; 単状糸球体腎炎

Vitamin D is a steroid hormone that plays an important role in the maintenance of calcium and mineral metabolism. The 24-hydroxylase (CYP24) enzyme is a cytochrome P450 molecule that is distributed in the target tissues of vitamin D, and is induced specially by 1α, 25 dihydroxyvitamin D_3.Two functions of this enzyme have been revealed so far. One is production of 24, 25 dihydroxyvitamin D_3 from 25-hydroxyvitamin D_3 as a substrate. 24, 25-dihydroxyvitamin D_3 is known to have an effect on bone mass increments when high doses to rats. The other function of CYP24 is to inactivate 1α, 25 dihydroxyvitamin D_3 which strongly induces this enzyme, and to maintain vitamin D homeostasis. In order to clarify the physiological role of CYP24 in vivo, we have over expressed CYP24 in rats. In the present study we examined the mechanism for the alteration in serum vitamin D metabolites levels and analysed the consequent influences on bone metabolism. In CYP24 transgenic rat, we found Out that excessive alubuminures developed from early stages, and as albumin has an ability to bind megalin, a receptor for vitamin D-binding protein. The excretion of 25-hydroxyvitamin D3 in Tg rats increased as albumin excretion increased, and both parameters had a strong positive correlation. Finally we examined the influence of renal dysfunction on bone metabolism. There was a significant decrease in bone mineral density of Tg rats at 8 weeks of age when the serum parathyroid hormone level begins to rise. Infusion of 25-hydroxyvitamin D3 greatly increased the BMD in the tibia of Tg rats. The mechanisms of CYP24 overexpression for induction of nephritis need to be elucidated in future studies.

维生素D是一种类固醇激素，在维持钙和矿物质代谢方面起着重要作用。24-羟化酶（CYP 24）是分布于维生素D靶组织的细胞色素P450分子，受1α，25-二羟维生素D_3的特异性诱导。一种是以25-羟基维生素D_3为底物生产24，25-二羟基维生素D_3。24，25-二羟维生素D_3在大剂量时对大鼠的骨量增加有影响。CYP 24的另一功能是合成1α，25-二羟维生素D_3，并维持维生素D的稳态。为了阐明CYP 24在体内的生理作用，我们在大鼠中过表达CYP 24。在本研究中，我们研究了血清维生素D代谢产物水平的变化机制，并分析了对骨代谢的影响。在CYP 24转基因大鼠中，我们发现过量的白蛋白从早期就开始形成，并且白蛋白具有结合巨蛋白的能力，巨蛋白是维生素D结合蛋白的受体。25-羟基维生素D3在Tg大鼠中的排泄量随着白蛋白排泄量的增加而增加，并且这两个参数具有很强的正相关性。最后，我们研究了肾功能不全对骨代谢的影响。有一个显着降低骨密度的Tg大鼠在8周龄时，血清甲状旁腺激素水平开始上升。输注25-羟基维生素D3可显著增加Tg大鼠胫骨的BMD。CYP 24过度表达诱导肾炎的机制需要在未来的研究中阐明。

项目成果

新木 敏正: "25-ヒドロキシビタミンD_3-1α-水酸化酵素の発現調節について"日本臨床. (製本中). (2002)

Toshimasa Araki：“25-羟基维生素 D_3-1α-羟化酶的表达调节”日本临床研究（书籍正在出版）。

細金直文, 新木敏正: "新・分子骨代謝学と骨粗鬆症"メディカルレビュー社. 513 (2001)

Naofumi Hosogane、Toshimasa Araki：“新分子骨代谢与骨质疏松症”医学评论出版 513（2001）。

Itoh, K., et al.: "Importance of membrane-or matrix-associated forms of m-CSF and RANKL/ODF in osteoclastogenesis by SaOS-4/3 cells expressing recombinant PTH/PTHrP receptors"J.Bone Miner.Res. 15・9. 1766-1775 (2000)

Itoh, K. 等人：“m-CSF 和 RANKL/ODF 的膜或基质相关形式在表达重组 PTH/PTHrP 受体的 SaOS-4/3 细胞破骨细胞生成中的重要性”J.Bone Miner.Res。 15・9。1766-1775（2000）

Masuno, H. et al.: "Rational Design, Synthesis and Biological Activity of Novel Conformationa11y Restricted Vitamin D Analogs, (22R)-and (22S)-22-Ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D_3"J.Med.Chem.. 45(in press). (2002)

Masuno, H. 等人：“新型构象限制性维生素 D 类似物 (22R)-和 (22S)-22-乙基-1,25-二羟基-23,24-二脱氢-24a 的合理设计、合成和生物活性

Wang, X. et al.: "Effects of geranylgeranoic acid in bone : induction of osteoblast differentiation and inhibition of osteoclast formation"J. Bone Miner. Res.. 17・1. 91-100 (2002)

Wang, X.等：“香叶基香叶酸对骨的影响：诱导成骨细胞分化和抑制破骨细胞形成”J. Bone Miner. 17・1 (2002)。