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-1alpha-hydroxylase (CYP27B1).
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.
Dardenne
O
O
Genetics Unit, Shriners Hospital for Children, Montreal, Quebec H3G 1A6, Canada.
Prud'homme
J
J
Hacking
S A
SA
Glorieux
F H
FH
St-Arnaud
R
R
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001842:Bone and Bones / Q000473:pathology* / Q000503:physiopathology; D002136:Calcium, Dietary / Q000627:therapeutic use; D004032:Diet; D006706:Homeostasis / Q000502:physiology; D006961:Hyperparathyroidism / Q000178:diet therapy / Q000209:etiology; D006996:Hypocalcemia / Q000178:diet therapy / Q000209:etiology; D007785:Lactose / Q000008:administration & dosage; D008297:Male; D051379:Mice; D023421:Models, Animal; D010758:Phosphorus / Q000008:administration & dosage; D012279:Rickets / Q000150:complications / Q000178:diet therapy*; D014808:Vitamin D Deficiency / Q000201:enzymology / Q000235:genetics
D002136:Calcium, Dietary; D010758:Phosphorus; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D007785:Lactose