Bouillon Roger, Carmeliet Geert, Verlinden Lieve, van Etten Evelyne, Verstuyf Annemieke, Luderer Hilary F, Lieben Liesbet, Mathieu Chantal, Demay Marie
Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and Endocrinology, Herestraat 49, O&N 1 bus 902, 3000 Leuven, Belgium.
Endocr Rev. 2008 Oct;29(6):726-76. doi: 10.1210/er.2008-0004. Epub 2008 Aug 11.
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.
维生素D内分泌系统对钙和骨骼稳态至关重要。通过对维生素D受体（VDR）基因工程缺失小鼠的批判性分析，现在可以更好地评估维生素D激素1,25 - 二羟基维生素D [1,25-(OH)(2)D]的精确作用模式和全部活性谱。小鼠体内缺乏功能性VDR或关键激活酶25 - OHD - 1α - 羟化酶（CYP27B1）会产生一种骨骼和生长板表型，类似于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的关键靶器官，因为高钙摄入或肠道中VDR的选择性恢复可使骨骼和生长板表型恢复正常。VDR几乎在所有组织中都有表达，几乎所有细胞都对1,25-(OH)(2)D暴露有反应；小鼠或人类基因组中约3%直接和/或间接受维生素D内分泌系统调控，这表明其功能更为广泛。VDR缺陷小鼠而非维生素D或1α - 羟化酶缺陷小鼠和人类会出现完全脱发，这表明VDR及其配体的功能并不完全重叠。VDR或维生素D缺陷小鼠的免疫系统总体正常，但在接触诱发因素后，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缺陷小鼠不会自发出现癌症增加，但更容易发生癌基因或化学致癌物诱导的肿瘤。它们还会出现高肾素性高血压、心脏肥大和血栓形成增加。正如VDR基因敲除表型所预测的那样，人类维生素D缺乏与疾病患病率增加有关。需要进行具有多个非血钙终点的前瞻性维生素D补充研究，以确定最佳维生素D状态的益处。
