The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1alpha-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)(2)D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1alpha-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.

中文翻译：

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维生素 D 与人类健康：维生素 D 受体缺失小鼠的经验教训。

维生素 D 内分泌系统对于钙和骨骼稳态至关重要。维生素 D 激素 1,25-二羟基维生素 D [1,25-(OH)(2)D] 的精确作用方式和全谱活性现在可以通过对工程缺失小鼠的批判性分析来更好地评估维生素 D 受体 (VDR)。小鼠体内缺乏功能性 VDR 或关键激活酶 25-OHD-1α-羟化酶 (CYP27B1) 会产生骨骼和生长板表型，模仿患有相同先天性疾病或严重维生素 D 缺乏症的人类。肠道是 VDR 的关键目标，因为高钙摄入量或肠道中的选择性 VDR 拯救可以恢复正常的骨骼和生长板表型。VDR 几乎无处不在，几乎所有细胞都对 1,25-(OH)(2)D 暴露有反应；大约 3% 的小鼠或人类基因组由维生素 D 内分泌系统直接和/或间接调节，表明其具有更广泛的功能。VDR 缺陷小鼠，而不是维生素 D 或 1α-羟化酶缺陷小鼠，和人类发生完全脱发，表明 VDR 及其配体的功能不完全重叠。缺乏 VDR 或维生素 D 的小鼠的免疫系统基本正常，但在暴露于易感因素后，对自身免疫性疾病（如炎症性肠病或 1 型糖尿病）的敏感性增加。VDR 缺陷小鼠的癌症不会自发增加，但更容易发生致癌基因或化学致癌物诱导的肿瘤。他们还会出现高肾素高血压、心脏肥大和血栓形成性增加。正如 VDR 无效表型所预测的那样，人类维生素 D 缺乏与疾病患病率的增加有关。需要具有多个非钙血症终点的前瞻性维生素 D 补充研究来确定最佳维生素 D 状态的益处。