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 D1

• Published in: Endocrinology (Philadelphia) Vol. 141; no. 7; pp. 2658 - 2666
• Main Authors: St-Arnaud, René, Arabian, Alice, Travers, Rose, Barletta, Frank, Raval-Pandya, Mihali, Chapin, Kelli, Depovere, Jos, Mathieu, Chantal, Christakos, Sylvia, Demay, Marie B, Glorieux, Francis H
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.07.2000
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.141.7.7579

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.