Inactivation of the 25-hydroxyvitamin D 1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis
Inactivation of the 25-hydroxyvitamin D 1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis
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DOI：
10.1074/jbc.m310271200
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发表时间：
2004-04-16
影响因子：
4.8
通讯作者：
Goltzman, D
中科院分区：
文献类型：
--
作者：
Panda, DK;Miao, DS;Goltzman, D
我们采用遗传学方法来确定1，25-二羟维生素D（1，25（OH）（2）D）缺乏和维生素D受体（VDR）缺乏是否会引起骨骼和钙稳态的相同改变，以及钙是否可以辅助1，25（OH）（2）D和VDR的骨骼功能。25-羟维生素D1 α-羟化酶靶向缺失的小鼠（1 α（OH）ase（-/-））基因、VDR基因和这两种基因暴露于1）高钙摄入，这维持了生育能力，但使小鼠低钙; 2）这种摄入加上每周三次注射1，25（OH）（2）D-3，仅使1 α（OH）ase（-/-）小鼠的钙正常化;或3）“拯救”饮食，其使所有突变体中的钙正常化。这些方案诱导不同的表型变化，从而揭示了钙和维生素D系统的选择性调节。甲状旁腺的大小和软骨生长板的发育分别受钙和1，25（OH）（2）D-3的调节，但不依赖于VDR。甲状旁腺激素分泌和骨矿化反映周围的钙水平，而不是1，25（OH）（2）D/VDR系统。相反，增加的钙吸收和最佳的成骨细胞和破骨细胞的生成是由1，25（OH）（2）D/VDR系统调节的。这些研究表明，钙离子和1，25（OH）（2）D/VDR系统对骨骼和钙稳态产生独立的影响，可能协同或独立发生。
We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)(2)D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha(OH) ase (-/-)) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25( OH)(2)D-3, which normalized calcium in the 1alpha(OH) ase (-/-) mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)(2)D-3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH)(2)D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH)(2)D/VDR system. These studies indicate that the calcium ion and the 1,25(OH)(2)D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.