title: Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D.
abstract: The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a targeted inactivating mutation of the 24-OHase gene had impaired 1,25(OH)2D catabolism. Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)2D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development.
authors.affiliation: Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada. rst-arnaud@shriners.mcgill.ca
authors.forename: R
authors.initials: R
authors.lastname: St-Arnaud
authors.forename: A
authors.initials: A
authors.lastname: Arabian
authors.forename: R
authors.initials: R
authors.lastname: Travers
authors.forename: F
authors.initials: F
authors.lastname: Barletta
authors.forename: M
authors.initials: M
authors.lastname: Raval-Pandya
authors.forename: K
authors.initials: K
authors.lastname: Chapin
authors.forename: J
authors.initials: J
authors.lastname: Depovere
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.forename: S
authors.initials: S
authors.lastname: Christakos
authors.forename: M B
authors.initials: MB
authors.lastname: Demay
authors.forename: F H
authors.initials: FH
authors.lastname: Glorieux
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000172:deficiency*; D000483:Alleles; D000818:Animals; D015519:Bone Density; D002117:Calcitriol / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006824:Hybridization, Genetic; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D051381:Rats; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics; D013250:Steroid Hydroxylases / Q000172:deficiency* / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D018167:Receptors, Calcitriol; D015650:24,25-Dihydroxyvitamin D 3; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol