Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D
Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D
复制标题
DOI：
10.1210/en.141.7.2658
复制
发表时间：
2000-07-01
期刊：
影响因子：
4.8
通讯作者：
Glorieux, FH
中科院分区：
文献类型：
--
作者：
St-Arnaud, R;Arabian, A;Glorieux, FH
25-羟基维生素 D-24-羟化酶 (24-OHase) 负责 1,25-二羟基维生素 D [1,25(OH)(2)D]（维生素 D 的活性形式）的分解代谢。24-OHase 酶还可以作用于 25-羟基维生素 D 底物，生成 24,25-二羟基维生素 D，这种代谢物的生理重要性尚不清楚。我们报告说，具有 24-OHase 基因靶向失活突变的小鼠的 1,25(OH)(2)D 分解代谢受损。令人惊讶的是，发育过程中 24-OHase 活性完全缺失会导致膜内骨矿化受损。通过将 24-OHase 突变小鼠与维生素 D 受体基因中含有靶向突变的小鼠杂交，可以挽救这种表型，证实通过维生素 D 受体起作用的升高的 1,25(OH)(2)D 水平是观察到的类骨质积累的原因。我们的结果证实了 24-OHase 酶对于维持维生素 D 稳态的生理重要性，并且表明 24,25-二羟基维生素 D 是骨骼发育过程中不可或缺的代谢物。
The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)(2)D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a targeted inactivating mutation of the 24-OHase gene had impaired 1,25(OH)(2)D catabolism. Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)(2)D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development.