title: Compensatory Changes in Calcium Metabolism Accompany the Loss of Vitamin D Receptor (VDR) From the Distal Intestine and Kidney of Mice.
abstract: 1,25 Dihydroxyvitamin D3 (1,25(OH)2 D) increases intestinal Ca absorption when dietary Ca intake is low by inducing gene expression through the vitamin D receptor (VDR). 1,25(OH)2 D-regulated Ca absorption has been studied extensively in the small intestine, but VDR is also present in the large intestine. Our goal was to determine the impact of large intestinal VDR deletion on Ca and bone metabolism. We used transgenic mice expressing Cre-recombinase driven by the 9.5-kb human caudal type homeobox 2 (CDX2) promoter to delete floxed VDR alleles from the caudal region of the mouse (CDX2-KO). Weanling CDX2-KO mice and control littermates were fed low (0.25%) or normal (0.5%) Ca diets for 7 weeks. Serum and urinary Ca, vitamin D metabolites, bone parameters, and gene expression were analyzed. Loss of the VDR in CDX2-KO was confirmed in colon and kidney. Unexpectedly, CDX2-KO had lower serum PTH (-65% of controls, p < 0.001) but normal serum 1,25(OH)2 D and Ca levels. Despite elevated urinary Ca loss (eightfold higher in CDX2-KO) and reduced colonic target genes TRPV6 (-90%) and CaBPD9k (-80%) mRNA levels, CDX2-KO mice had only modestly lower femoral bone density. Interestingly, duodenal TRPV6 and CaBPD9k mRNA expression was fourfold and threefold higher, respectively, and there was a trend toward increased duodenal Ca absorption (+19%, p = 0.076) in the CDX2-KO mice. The major finding of this study is that large intestine VDR significantly contributes to whole-body Ca metabolism but that duodenal compensation may prevent the consequences of VDR deletion from large intestine and kidney in growing mice.
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Perla C
authors.initials: PC
authors.lastname: Reyes-Fernandez
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007420:Intestine, Large / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium
keywords: CA METABOLISM; CDX2P9.5; LARGE INTESTINE; VITAMIN D; VITAMIN D RECEPTOR