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.
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.
St-Arnaud
R
R
Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada. rst-arnaud@shriners.mcgill.ca
Arabian
A
A
Travers
R
R
Barletta
F
F
Raval-Pandya
M
M
Chapin
K
K
Depovere
J
J
Mathieu
C
C
Christakos
S
S
Demay
M B
MB
Glorieux
F H
FH
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
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