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1,25-Dihydroxyvitamin D₃ Regulates the Expression of Low-Density Lipoprotein Receptor-Related Protein 5 via Deoxyribonucleic Acid Sequence Elements Located Downstream of the Start Site of Transcription

Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: J. Wesley Pike, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706. E-mail: pike{at}biochem.wisc.edu.

The skeleton is a direct target of vitamin D action, where the hormone modulates the proliferation of osteoblast precursors, their differentiation into mature osteoblasts, and their functional activity. Some of these effects of vitamin D are reminiscent of those orchestrated by the Wnt signaling pathway wherein stimulation of the membrane receptor Frizzled and its coreceptor LRP5 leads to activation of ß-catenin and subsequent transcription-mediated changes in osteoblast biology. Indeed, LRP5 is now known to play a particularly important role in bone formation such that the loss of this component results in a reduction in osteoblast number, a delay in mineralization, and a reduction in peak bone mineral density. Interestingly, we discovered during the course of a vitamin D receptor (VDR) chromatin immunoprecipitation/DNA microarray analysis that 1,25-(OH)₂D₃ could induce binding of the VDR to sites within the Lrp5 gene locus. VDR and retinoid X receptor binding was evident both in primary osteoblasts as well as in osteoblasts of cell line origin. Importantly, this interaction between 1,25-(OH)₂D₃-activated VDR and the Lrp5 gene led to both a modification in chromatin structure within the Lrp5 locus and the induction of Lrp5 mRNA transcripts in vivo as well as in vitro. One of these sites within the Lrp5 locus was discovered to confer vitamin D response to a heterologous promoter when introduced into osteoblastic cells, permitting both the identification and characterization of the vitamin D response element located within. Interestingly, additional studies revealed that whereas the regulatory region in the mouse Lrp5 gene was highly conserved in the human genome, the vitamin D response element was not. Our studies show that 1,25-(OH)₂D₃ can enhance the expression of a critical component of the Wnt signaling pathway that is known to impact osteogenesis.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Ligands:   Calcitriol

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