In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 1 ( 2006-01-03), p. 75-80
Abstract:
The hormonally active form of vitamin D 3 ,1α,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 -1α-hydroxylase (1α-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 1α-hydroxylase gene is replaced by the genes for β-galactosidase ( lacZ ) and neomycin resistance. Null mice produced no detectable 1α-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 , β-galactosidase activity was detected in the kidneys of the –/– and +/– mice and in placentas harvested from –/– females bred with –/– males. No β-galactosidase activity was detected in skin sections or in primary keratinocyte cultures from –/– animals. Our results demonstrate we have generated 1α-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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0509734103
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2006
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink