title: 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.
abstract: 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)2D3. 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-/- mice and heterozygote controls were treated with 500 pg of 1,25(OH)2D/g body weight/day for 2 weeks, followed by 100 pg of 1,25(OH)2D3/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)2D3 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)2D3 metabolite is effective to rescue the PDDR phenotype of 1alpha-OHase mutant mice.
authors.affiliation: Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dardenne
authors.forename: Josée
authors.initials: J
authors.lastname: Prudhomme
authors.forename: S Adam
authors.initials: SA
authors.lastname: Hacking
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: René
authors.initials: R
authors.lastname: St-Arnaud
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002117:Calcitriol / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010018:Osteomalacia / Q000188:drug therapy; D010641:Phenotype; D012279:Rickets / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013250:Steroid Hydroxylases / Q000235:genetics; D014808:Vitamin D Deficiency / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol