Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 1, Pages 75-80Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0509734103
Keywords
extrarenal 1,25-dihydroxyvitamin D-3
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The hormonally active form of vitamin D-3, 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], is synthesized in the kidney through a tightly regulated reaction catalyzed by 25-hydroxyvitamin D-3-1 alpha-hydroxylase (la-hydroxylase), the product of the CYP27B1 gene. Through gene targeting in embryonic stem cells, we engineered a mouse strain in which the coding region of the la-hydroxylase gene is replaced by the genes for beta-galactosidase (IacZ) and neomycin resistance. Null mice produced no detectable la-hydroxylase transcript. The mice grew normally when maintained on a balanced diet containing 1,25(OH)(2)D-3 but rapidly developed rickets when phosphorus and 1,25(OH)(2)D-3 were restricted. Rickets was curable through administration of 1,25(OH)(2)D-3 but not its biological precursor, 25-hydroxyvitamin D-3. Upon administration of a diet low in calcium and devoid of any form of vitamin D-3, beta-galactosiclase activity was detected in the kidneys of the -/- and mice and in placentas harvested from -/- females bred with males. No beta-galactosidase activity was detected in skin sections or in primary keratinocyte cultures from -/- animals. Our results demonstrate we have generated 1 alpha-hydroxylase null mice that display phenotypes characteristic of vitamin D-dependency rickets type I. From the histochemical analysis of reporter gene expression in these mice, we conclude that acute 1,25(OH)(2)D-3 deficiency in otherwise healthy animals does not stimulate local production of 1,25(OH)(2)D-3 in the skin. These findings stand in contrast to previously published reports of 1,25(OH)(2)D-3 production in keratinocytes.
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