Mechanisms for the reduction of 24,25-dihydroxyvitamin D3 levels and bone mass in 24-hydroxylase transgenic rats
Mechanisms for the reduction of 24,25-dihydroxyvitamin D3 levels and bone mass in 24-hydroxylase transgenic rats
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DOI：
10.1096/fj.02-0965fje
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发表时间：
2003-02-01
期刊：
影响因子：
4.8
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Hosogane, N;Shinki, T;Suda, T
24-羟化酶 (CYP24) 是一种分布在 1α,25-二羟基维生素 D-3 [1α,25(OH)(2)D-3] 靶组织中的酶。已报道了该酶的两种功能：一种是产生 24,25-二羟基维生素 D-3 [24,25(OH)(2)D-3]，另一种是 1α,25(OH)(2)D-3 的失活。为了阐明 CYP24 在体内的其他生理作用，我们之前培育了组成型表达 CYP24 基因的大鼠。这些转基因 (Tg) 大鼠出现了意想不到的表型，例如血浆 24,25(OH)(2)D-3 水平低、脂血症和蛋白尿。在这项研究中，我们阐明了诱导低血浆 24,25(OH)(2)D-3 水平和骨质流失的机制。 Tg 大鼠分泌大量维生素 D 结合蛋白 (DBP)，这与白蛋白的损失同时发生。在 Tg 大鼠中，巨蛋白的肾脏表达模式与野生型大鼠相同，巨蛋白作为一种内吞受体，负责尿蛋白（如 DBP 和白蛋白）的再摄取。排泄的白蛋白似乎与巨蛋白竞争 DBP-25-羟基维生素 D-3 [25(OH)D-3] 复合物的结合和重吸收，导致 25(OH)D-3 流失到尿液中，随后血浆 24,25(OH)(2)D-3 减少。在这种著名的肾炎大鼠模型中，补充 25(OH)D-3 可有效预防肾功能不全早期的骨质流失。
24-Hydroxylase (CYP24) is an enzyme distributed in the target tissues of 1alpha,25-dihydroxyvitamin D-3 [1alpha,25(OH)(2)D-3]. Two functions for this enzyme have been reported: One is production of 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] and the other is inactivation of 1alpha,25(OH)(2)D-3. To elucidate other physiologic roles of CYP24 in vivo, we previously generated rats that constitutively express the CYP24 gene. These transgenic (Tg) rats developed unexpected phenotypes, such as low plasma levels of 24,25(OH)(2)D-3, lipidemia, and albuminuria. In this study, we elucidated the mechanisms for inducing low plasma 24,25(OH)(2)D-3 levels and bone loss. Tg rats excreted massive amounts of vitamin D binding protein (DBP), which coincided with the loss of albumin. In Tg rats, the renal expression pattern of megalin, which serves as an endocytotic receptor responsible for the reuptake of urinary proteins such as DBP and albumin, was identical to that of the wild-type rats. Excreted albumin appeared to compete for the binding and reabsorption of the DBP-25-hydroxyvitamin D-3 [25(OH)D-3] complex with megalin, resulting in a loss of 25(OH)D-3 into the urine and subsequent reduction of plasma 24,25(OH)(2)D-3. In this prominent rat model of nephritis, supplementation of 25(OH)D-3 was effective in preventing bone loss in an early stage of renal insufficiency.