Molecular analysis of vitamin D receptor defect and regulation of expression of vitamin D action

维生素 D 受体缺陷的分子分析及维生素 D 作用表达的调控

基本信息

批准号：
04670601
负责人：
TAKEDA Eiji
金额：
$ 1.34万
依托单位：
University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670601/
关键词：
Vitamin D Vitamin D receptor Osteocalcin Transcriptional regulation Vitamin D dependent rickets type II ビタミンD依存性くる病2型

项目摘要

Vitamin D receptor(VDR) is a nuclear transcription factor which binds to vitamin D response element(VDRE) of human osteocalcin gene and regulates expression. Human VDR defect shouws clinical heterogeneity among patients with the same point mutation their VDR gene. In addition, rickets did not recur after the cessation of therapy during 6 to 24 years of follow up. To elucidate these clinical findings, the complex formations of VDRE and nuclear extracts of cultured skin fibroblasts treated with 1,25-dihydroxyvitamin D_3(1,25(OH)_2D_3), retinoic acid(RA) and/or triiodothyronine(T3) were investigated as a molecular parameters of transcriptional activity. The complex formation in control cells was increased by the treatment of either 0.1nM, 1nM, 10nM 1,25(OH)_2D_3, 100nM RA or 100nM T3, however additive effect of these combinations was not found. In patient's cells, either 1,25(OH)_2D_3, RA or T3 increased the complex formation, while neither combination also additively stimulated. These results indicated that 1,25(OH)_2D_3. RA and T3 had some role in the regulation of bone remodeling through modulating osteocalcin expression. Therefore, clinical observation in patients with VDR defect might be at least patrly explained by overlapping control in the regulation of osteocalcin expession.

维生素D受体(VDR)是一种核转录因子，与人骨钙素基因的维生素D反应元件(VDRE)结合并调节表达。人类 VDR 缺陷显示出具有相同 VDR 基因点突变的患者之间的临床异质性。此外，在6至24年的随访期间，停止治疗后佝偻病并未复发。为了阐明这些临床发现，我们研究了用 1,25-二羟基维生素 D_3(1,25(OH)_2D_3)、视黄酸 (RA) 和/或三碘甲状腺原氨酸 (T3) 处理的培养皮肤成纤维细胞的 VDRE 和核提取物的复杂结构。作为转录活性的分子参数。对照细胞中的复合物形成通过0.1nM、1nM、10nM 1,25(OH)_2D_3、100nM RA或100nM T3的处理而增加，但是没有发现这些组合的累加效应。在患者的细胞中，1,25(OH)_2D_3、RA 或 T3 都会增加复合物的形成，而这两种组合都不会产生附加刺激。这些结果表明1,25(OH)_2D_3。 RA和T3通过调节骨钙素表达在骨重塑调节中发挥一定作用。因此，VDR 缺陷患者的临床观察至少可以部分地通过骨钙素表达调节的重叠控制来解释。