Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.
Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.
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低磷血症小鼠中甲状旁腺激素异常刺激 25-羟基维生素 D-1 α-羟化酶活性。
DOI：
10.1172/jci112274
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
Lobaugh,B
中科院分区：
文献类型：
--
作者：
Nesbitt,T;Drezner,MK;Lobaugh,B
维生素D代谢的异常调节是人类x连锁低磷佝偻病和低磷（Hyp）小鼠疾病的小鼠同源物的特征。我们之前报道过突变小鼠的肾25-羟基维生素D-1 α -羟化酶（1 α -羟化酶）活性在低磷血症的普遍程度下异常低。为了进一步表征这一缺陷，我们检查了hyp小鼠肾1 α -羟化酶活性是否对酶功能的其他刺激和抑制控制正常反应。我们研究了甲状旁腺激素（PTH）的刺激：(a)钙缺乏（0.02% Ca）的饮食增加内源性PTH；或(b)通过渗透微型泵连续输注0.25 IU/h牛甲状旁腺激素24小时。在这两种情况下，相同处理的正常小鼠的酶活性增加到比hyph小鼠更高的水平。PTH刺激1 α -羟化酶活性的相对无能不是hyph小鼠低磷血症的功能，因为PTH注入，磷酸盐耗尽的正常小鼠维持的酶活性水平高于正常小鼠和hyph小鼠。在进一步的研究中，我们通过使用：(a)含钙（1.2% Ca）的饮食来抑制内源性甲状旁腺激素；或(b) 24小时连续输注0.2 ng/h 1,25-二羟基维生素D3 （1,25(OH)2D3）。正常小鼠和高钙小鼠的1 α -羟化酶活性在维持高钙饮食后显著降低到相似的绝对水平。此外，输注125 (OH)2D3在正常、Hyp-和磷酸盐耗尽的正常小鼠中引起1 α -羟化酶活性的类似降低。这些观察结果表明，通过降低PTH水平或增加1,25(OH)2D3浓度对1 α -羟化酶的抑制控制在突变体中是完整的。然而，PTH和低磷血症不能以类似于正常小鼠和磷酸盐耗尽小鼠的方式刺激酶活性，这表明在低磷小鼠中表现出1 α -羟化酶调节的普遍缺陷。
Abnormal regulation of vitamin D metabolism is a feature of X-linked hypophosphatemic rickets in man and of the murine homologue of the disease in the hypophosphatemic (Hyp)-mouse. We previously reported that mutant mice have abnormally low renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal 1 alpha-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calcium-deficient (0.02% Ca) diet to raise endogenous PTH; or (b) 24-h continuous infusion of 0.25 IU/h bovine PTH via osmotic minipump. In both cases enzyme activity of identically treated normal mice increased to greater levels than those attained by Hyp-mice. The relative inability of PTH to stimulate 1 alpha-hydroxylase activity is not a function of the hypophosphatemia in the Hyp-mouse since PTH-infused, phosphate-depleted normal mice sustained a level of enzyme activity greater than that of normal and Hyp-mice. In further studies we investigated inhibition of enzyme activity by using: (a) a calcium-loaded (1.2% Ca) diet to suppress endogenous PTH; or (b) 24-h continuous infusion of 0.2 ng/h 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The 1 alpha-hydroxylase activity of normal and Hyp-mice was significantly reduced to similar absolute levels following maintenance on the calcium-loaded diet. Further, infusion of 1,25(OH)2D3 caused a comparable reduction of 1 alpha-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of 1 alpha-hydroxylase by reduced levels of PTH or increased 1,25(OH)2D3 concentrations is intact in the mutants. However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates that a generalized defect of 1 alpha-hydroxylase regulation is manifest in Hyp-mice.
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