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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

Genetics Unit (R.St-A., A.A., R.T., F.H.G.), Shriners Hospital for Children, Montréal (Québec) Canada H3G 1A6; Departments of Surgery and Human Genetics (R.St-A., F.H.G.), McGill University, Montréal (Québec) Canada H3A 1B1; Department of Biochemistry and Molecular Biology (F.B., M.R.-P., S.C.), New Jersey Medical School, Newark, New Jersey 07103; Endocrine Unit (K.C., M.B.D.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Laboratorium voor experimentele geneeskunde en endocrinologie (J.D., C.M.), Catholic University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: René St-Arnaud, Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal (Québec), Canada H3G 1A6.

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.

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