Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1)
Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1)
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DOI：
10.1016/s8756-3282(03)00023-1
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发表时间：
2003-04-01
期刊：
影响因子：
4.1
通讯作者：
St-Arnaud, R
中科院分区：
文献类型：
--
作者：
Dardenne, O;Prud'homme, J;St-Arnaud, R
25-羟维生素D-1 α-羟化酶基因（CYP 27 B1; 1 α-OHase）突变可导致假性维生素D缺乏性佝偻病（PDDR），而维生素D受体（VDR）突变可导致遗传性维生素D抗性佝偻病。这两种疾病的动物模型已经被设计出来。通过高钙、高磷、高乳糖饮食喂养动物，可以完全挽救VDR消融小鼠的骨表型。我们试图通过高钙饮食来挽救1 α-羟化酶基因缺陷小鼠的PDDR表型。补救方案包括从3周龄至8.5周龄处死期间饲喂含2%钙、1.25%磷、20%乳糖的饲料（补救饲料）。血液生化分析显示，补救饮食纠正了低钙血症和继发性甲状旁腺功能亢进。尽管恢复了正常钙血症，但饲喂救援饲料的1alpha-OHase（-/-）（和1alpha-OHase（+/-））动物最初的体重增加速度低于饲喂正常小鼠饲料的对照小鼠。尽管喂食救援饲料的1alpha-OHase（-/-）小鼠最终达到与对照动物相同的体重，但治疗并没有完全纠正骨生长，因为股骨尺寸仍然显著小于对照组。骨组织学和组织形态计量学证实佝偻病和骨软化症治愈。补救饮食也恢复了正常参数内的骨组织的生物力学特性。这些结果表明，纠正异常的矿物质离子稳态喂养高钙救援饮食是有效的救援1 α-羟化酶突变小鼠的PDDR表型。然而，这种治疗似乎不如1，25（OH）（2）D-3替代疗法有效，因为骨生长仍然受损。(C)2003 Elsevier Science（美国）。All rights reserved.
Mutations in the 25-hydroxyvitamin D-1alpha-hydroxylase gene (CYP27B1; 1alpha-OHase) cause pseudo vitamin D deficiency rickets (PDDR), while mutations in the vitamin D receptor (VDR) cause hereditary vitamin D resistance rickets. Animal models of both diseases have been engineered. The bone phenotype of VDR-ablated mice can be completely rescued by feeding the animals with a high-calcium, high-phosphorus, high-lactose diet. We have attempted to rescue the PDDR phenotype of mice deficient for the 1alpha-OHase gene by feeding them with the high-calcium diet. The rescue regimen consisted of feeding a diet containing 2% calcium, 1.25% phosphorus, 20% lactose (rescue diet) from 3 weeks of age until sacrifice at 8.5 weeks of age. Blood biochemistry analysis revealed that the rescue diet corrected the hypocalcemia and secondary hyperparathyroidism. Despite the restoration of normocalcemia, 1alpha-OHase(-/-) (and 1alpha-OHase(+/-)) animals fed the rescue diet initially gained weight less rapidly than control mice fed normal mouse chow. Although 1alpha-OHase(-/-) mice fed the rescue diet eventually reached the same weight as control animals, the treatment did not entirely correct bone growth, as femur size remained significantly smaller than that of control. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue diet also restored the biomechanical properties of the bone tissue within normal parameters. These results demonstrate that correction of the abnormal mineral ion homeostasis by feeding with a high-calcium rescue diet is effective to rescue the PDDR phenotype of 1alpha-OHase mutant mice. This treatment, however, does not appear as effective as 1,25(OH)(2)D-3 replacement therapy since bone growth remained impaired. (C) 2003 Elsevier Science (USA). All rights reserved.