Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia
Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia
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DOI：
10.1073/pnas.94.18.9831
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发表时间：
1997-09-02
影响因子：
11.1
通讯作者：
DeMay, MB
中科院分区：
文献类型：
--
作者：
Li, YC;Pirro, AE;DeMay, MB
维生素 D 是控制矿物质离子稳态的主要类固醇激素，通过维生素 D 受体 (VDR) 发挥作用。VDR 在许多组织中表达，包括一些不被认为在矿物质代谢中发挥作用的组织。对具有 VDR 突变（维生素 D 依赖性佝偻病 II 型，VDDR II）的亲属进行的研究表明，会出现低钙血症、甲状旁腺功能亢进、佝偻病和骨软化症。脱发并非维生素 D 缺乏的症状，但在某些家族中也有出现。我们通过靶向消融 VDR DNA 结合域的第二个锌指，生成了 VDDR II 小鼠模型。尽管已知 VDR 在胎儿生命中表达，但纯合小鼠在出生时表型正常，并且至少在 6 个月之前表现出正常存活率。它们在 21 天时出现低钙血症，此时它们的甲状旁腺激素 (PTH) 水平开始上升。甲状旁腺功能亢进症伴随着甲状旁腺体积的增大以及 PTH mRNA 水平的增加。第 35 天出现佝偻病和骨软化症；然而，早在第 15 天，生长板中的肥大软骨细胞区域就出现了扩张。与通过饮食方式缺乏维生素 D 的动物不同，并且像一些患有 VDDR IT 的患者一样，这些小鼠从 4 周大起就会出现进行性脱发。
Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR), The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism, Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise, Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR IT, these mice develop progressive alopecia from the age of 4 weeks.