Rescue of the phenotype of CYP27B1 (1alpha-hydroxylase)-deficient mice.

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 (Endocrinology 142 (2001) 3135). Replacement therapy was performed in this model, and compared to feeding with a high calcium diet containing 2% calcium, 1.25% phosphorus, 20% lactose (rescue diet). Blood biochemistry analysis revealed that both rescue treatments corrected the hypocalcemia and secondary hyperparathyroidism. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured by both rescue protocols. However, despite the restoration of normocalcemia, the rescue diet did not entirely correct bone growth as femur size remained significantly smaller than control in 1alpha-OHase(-/-) mice fed the rescue diet. 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.