Evidence base treatment of renal osteodistropy

肾性骨营养不良的循证治疗

• 批准号: 17590066
• 负责人: SHINKI Toshimasa
• 金额: $ 2.3万
• 依托单位: Nihon Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590066/
• 关键词: Kidney; Renal osteodystrophy; Vitamin D; Parathyroid hormone; Transgenic; Bone mineral; Vitamin D metabolism; Proteomics; 石灰化; 骨吸収; 副甲状腺; カルシトニン; 腎炎; 糖尿病

24-Hydroxylase (CYP24) is an enzyme distributed in the target tissues of 1α,25-dihydroxyvitamin D_3 [1α,25(OH)_2D_3]. Two functions for this enzyme have been reported: One is production of 24,25-dihydroxyvitamin D_3 [24,25(OH)_2D_3] and the other is inactivation of 1α,25(OH)_2D_3. To elucidate other physiologic roles of CYP24 in vivo, we previously generated rats that constitutively express the CYP24 gene. These transgenic (Tg) rats developed unexpected phenotypes, such as low plasma levels of 24,25(OH)_2D_3, lipidemia, and albuminuria. In this study, we elucidated the mechanisms for inducing low plasma 24,25(OH)_2D_3 levels and bone loss. Tg rats excreted massive amounts of vitamin D binding protein (DBP), which coincided with the loss of albumin. In Tg rats, the renal expression pattern of megalin, which serves as an endocytotic receptor responsible for the reuptake of urinary proteins such as DBP and albumin, was identical to that of the wild-type rats. Excreted albumin appeared to compete for the binding and reabsorption of the DBP-25-hydroxyvitamin D_3 [25(OH)D_3] complex with megalin, resulting in a loss of 25(OH)D_3 into the urine and subsequent reduction of plasma 24,25(OH)_2D_3. In this prominent rat model of nephritis, supplementation of 25(OH)D_3 was effective in preventing bone loss in an early stage of renal insufficiency.

24-羟化酶（CYP 24）是1α，25-二羟维生素D_3 [1α，25（OH）_2D_3]的靶组织酶。该酶有两种功能：一种是产生24，25-二羟维生素D_3 [24，25（OH）_2D_3]，另一种是失活1α，25（OH）_2D_3。为了阐明CYP 24在体内的其他生理作用，我们先前产生了组成型表达CYP 24基因的大鼠。这些转基因（Tg）大鼠出现了意想不到的表型，如低水平的血浆24，25（OH）_2D_3，尿蛋白和尿蛋白。本研究阐明了低血浆24，25（OH）_2D_3水平和骨丢失的机制。Tg大鼠分泌大量的维生素D结合蛋白（DBP），这与白蛋白的丢失相一致。在Tg大鼠中，巨蛋白的肾脏表达模式与野生型大鼠相同，巨蛋白是一种负责尿蛋白（如DBP和白蛋白）再摄取的内吞受体。排出的白蛋白似乎与megalin竞争DBP-25-羟基维生素D_3 [25（OH）D_3]复合物的结合和重吸收，导致25（OH）D_3丢失到尿中，随后血浆24，25（OH）_2D_3减少。在这一显著的肾炎大鼠模型中，补充25（OH）D_3可有效地防止肾功能不全早期的骨丢失。

项目成果

Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts

• DOI: 10.1073/pnas.0505663103
• 发表时间: 2006-03-21
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Woo, JT;Kawatani, M;Osada, H
• 通讯作者: Osada, H

NEW生化学

NEW生物化学

• 发表时间: 2006
• 作者: Imai;H.;新木敏正 他
• 通讯作者: 新木敏正 他

Involvemnet of Tiam1 in apoptosis induced by bufalin in HeLa cells.

Tiam1 参与蟾毒灵诱导 HeLa 细胞凋亡。

• 发表时间: 2007
• 期刊: anticancer. Res. 27・1A
• 作者: Kazuo Negishi;Chie Otsuka他;Cao-Hong. et al.
• 通讯作者: Cao-Hong. et al.

Analogs of la,25-dihydroxyvitamin D3 with high potency in induction of osteoclastogenesis and prevention of dendritic cell differentiation : synthesis and biological evaluation of 2-substituted 19-norvitamin D analogs.

1a,25-二羟基维生素 D3 的类似物在诱导破骨细胞生成和预防树突细胞分化方面具有高效能：2-取代的 19-去甲维生素 D 类似物的合成和生物学评价。

• 发表时间: 2006
• 期刊: Bioorg Med Chem 14(13)
• 作者: Shimazaki;M.et al.
• 通讯作者: M.et al.