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)(2)D], the act ive form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvi tamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a target ed inactivating mutation of the 24-OHase gene had impaired 1,25(OH)(2)D cat abolism. Surprisingly, complete absence of 24-OHase activity during develop ment leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a target ed mutation in the vitamin D receptor gene, confirming that the elevated 1, 25(OH)(2)D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiolog ical importance of the 24-OHase enzyme for maintaining vitamin D homeostasi s, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolit e during bone development.