* Laboratory of Experimental Medicine and Endocrinology, Katholieke
Universiteit Leuven, Leuven, B-3000 Belgium;
Communicated by Robert H. Wasserman, Cornell University, Ithaca,
NY, September 7, 2001 (received for review March 4, 2001)
Rickets and hyperparathyroidism caused by a defective vitamin
D receptor (VDR) can be prevented in humans and animals by high calcium
intake, suggesting that intestinal calcium absorption is critical for
1,25(OH)2 vitamin D [1,25(OH)2D3]
action on calcium homeostasis. We assessed the rate of serum
45Ca accumulation within 10 min of oral gavage in two
strains of VDR-knockout (KO) mice (Leuven and Tokyo KO) and observed a
3-fold lower area under the curve in both KO strains. Moreover, we
evaluated the expression of intestinal candidate genes involved in
transcellular calcium transport. The calcium transport protein1 (CaT1)
was more abundantly expressed at mRNA level than the epithelial calcium channel (ECaC) in duodenum, but both were considerably reduced (CaT1>90%, ECaC>60%) in the two VDR-KO strains on a normal calcium diet. Calbindin-D9K expression was decreased only in the
Tokyo KO, whereas plasma membrane calcium ATPase (PMCA1b)
expression was normal in both VDR-KOs. In Leuven wild-type mice, a high
calcium diet inhibited (>90%) and 1,25(OH)2D3
injection or low calcium diet induced (6-fold) duodenal CaT1 expression
and, to a lesser degree, ECaC and calbindin-D9K expression.
In Leuven KO mice, however, high or low calcium intake decreased
calbindin-D9K and PMCA1b expression, whereas
CaT1 and ECaC expression remained consistently low on any diet. These
results suggest that the expression of the novel duodenal epithelial
calcium channels (in particular CaT1) is strongly vitamin D-dependent,
and that calcium influx, probably interacting with
calbindin-D9K, should be considered as a rate-limiting step
in the process of vitamin D-dependent active calcium absorption.
Medical Sciences
Duodenal calcium absorption in vitamin D receptor-knockout mice:
Functional and molecular aspects
,
,,,, Center for Transgene Technology and Gene Therapy,
Flanders Interuniversity Institute for Biotechnology, Herestraat 49, Leuven, B-3000 Belgium; Department of Cell
Physiology, Institute of Cellular Signaling, University Medical
Centre Nijmegen, NL-6500-HB The Netherlands; and
§ Institute of Molecular and Cellular Biosciences,
University of Tokyo, Bunkyo-Ku, Tokyo 113, Japan
¶
To whom reprint requests should be addressed. E-mail:
Geert.Carmeliet{at}med.kuleuven.ac.be.
www.pnas.org/cgi/doi/10.1073/pnas.231474698
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