Increased Vitamin D Receptor Level Enhances 1,25-dihydroxyvitamin D3-mediated Gene Expression and Calcium Transport in Caco-2 Cells

J Bone Miner Res. 2001 Apr;16(4):615-24. doi: 10.1359/jbmr.2001.16.4.615.

Abstract

Altered vitamin D receptor (VDR) level has been proposed to explain differences in intestinal responsiveness to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We tested whether the enterocyte VDR level influences 1,25(OH)2D3-mediated gene expression and transepithelial calcium (Ca) transport in the human intestinal cell line Caco-2. Cells were stably transfected with a human metallothionein (hMT) IIA promoter-human VDR (hVDR) complementary DNA (cDNA) transgene that overexpressed hVDR in response to heavy metals. In MTVDR clones, induction of 25-hyroxyvitamin D3-24-hydroxylase (24-OHase) messenger RNA (mRNA) expression by 1,25(OH)2D3 (10(-9) M, 4 h) was correlated to metal-induced changes in nuclear VDR level (r2 = 0.99). In MTVDR clones, basal VDR level was 2-fold greater and 1,25(OH)2D3-mediated Ca transport (10(-7) M, 24 h) was 43% higher than in parental Caco-2 cells. Treatment of MTVDR clones with Cd (1 microM, 28 h) increased VDR level by 68%, significantly enhanced 1,25(OH)2D3-mediated Ca transport by 24%, and increased accumulation of calbindin D9K mRNA by 76% relative to 1,25(OH)2D3 alone. These observations support the hypothesis that the enterocyte VDR level is an important modulator of intestinal responsiveness to 1,25(OH)2D3.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Caco-2 Cells
  • Cadmium / pharmacology
  • Calbindins
  • Calcitriol / pharmacology*
  • Calcium / metabolism*
  • DNA, Complementary / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects*
  • Genes, Synthetic
  • Humans
  • Ion Transport / drug effects
  • Metallothionein / genetics
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / biosynthesis
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / physiology*
  • Recombinant Fusion Proteins / physiology
  • S100 Calcium Binding Protein G / biosynthesis
  • S100 Calcium Binding Protein G / genetics
  • Stimulation, Chemical
  • Transfection
  • Transgenes
  • Zinc / pharmacology

Substances

  • Calbindins
  • DNA, Complementary
  • RNA, Messenger
  • Receptors, Calcitriol
  • Recombinant Fusion Proteins
  • S100 Calcium Binding Protein G
  • S100G protein, human
  • Cadmium
  • Metallothionein
  • Calcitriol
  • Zinc
  • Calcium