Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3:: Biochemical, histomorphometric, and biomechanical analyses
Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3:: Biochemical, histomorphometric, and biomechanical analyses
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DOI：
10.1359/jbmr.2003.18.4.637
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发表时间：
2003-04-01
影响因子：
6.2
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
假性维生素D缺乏性佝偻病（PDDR）是由25-羟基维生素D-1 α-羟化酶（CYP 27 B1;1alpha-OHase）基因突变引起的，其治疗选择是1，25（OH）（2）D-3替代疗法。我们先前已经通过在小鼠中靶向失活1 α-OHase基因来设计PDDR的动物模型。在该模型中进行替代治疗。1 α-OHase（-1-）小鼠和杂合子对照组在8周龄死亡前，每天给予500 pg 1，25（OH）（2）D-3/g体重，持续2周，然后每天给予100 pg 1，25（OH）（2）D-3/g体重，持续3周。血液生化分析显示，补救治疗纠正了低钙血症和继发性甲状旁腺功能亢进。每日注射1，25（OH）（2）D-3诱导CYP 24（25-羟基维生素D 24-羟化酶基因）的强烈表达。骨组织学和组织形态计量学证实佝偻病和骨软化症治愈。补救方案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，活性1，25（OH）（2）D-3代谢物长期治疗可有效挽救1 α-OHase突变小鼠的PDDR表型。
The treatment of choice for pseudo-vitamin D deficiency rickets (PDDR), caused by mutations in the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1;1alpha-OHase) gene, is replacement therapy with 1,25(OH)(2)D-3. We have previously engineered an animal model of PDDR by targeted inactivation of the 1alpha-OHase gene in mice. Replacement therapy was performed in this model. The 1alpha-OHase(-1-) mice and heterozygote controls were treated with 500 pg of 1,25(OH)(2)D-3/g body weight/day for 2 weeks, followed by 100 pg of 1,25(OH)(2)D-3/g body weight/day for an additional 3 weeks before death at 8 weeks of age. Blood biochemistry analysis revealed that the rescue treatment corrected the hypocalcemia and secondary hyperparathyroidism. The daily injections of 1,25(OH)(2)D-3 induced strong expression of CYP24, the 25-hydroxyvitamin D 24-hydroxylase gene. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue regimen also restored the biomechanical properties of the bone tissue within normal parameters. These results show that chronic treatment with the active 1,25(OH)(2)D-3 metabolite is effective to rescue the PDDR phenotype of 1alpha-OHase mutant mice.