Specificity and flexibility of vitamin D signaling. Modulation of the activation of natural vitamin D response elements by thyroid hormone.

Cellular responsiveness to 1,25-dihydroxyvitamin D3 (VD) is conferred by its intracellular receptor (VDR), which belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. VDRs are known to bind to specific response elements in the promoter region of VD-regulated genes. Two types of natural VD response elements (VDREs) have been identified so far. One is bound by VDR homodimers and is found in the human osteocalcin gene promoter (DR6-type), and the other is bound by heterodimers of VDR with retinoid X receptors (RXRs) as in the mouse osteopontin promoter (DR3-type). Here, we demonstrate that VDRs directly interact in solution not only with RXR but also with retinoid acid receptors (RARs) and, interestingly, with thyroid hormone receptors (T3Rs). All three heterodimeric partners were able to enhance the in vitro DNA binding affinity of VDR as compared to VDR homodimers, but they showed different affinities for the two types of VDREs, as determined by Scatchard analysis. Moreover, functional assays showed that VDR.T3R heterodimers act differently on the two types of VDREs; on the DR3-type we observed highest induction by thyroid hormone (3,5,3'-triiodothyronine, T3) alone, whereas on a DR6-type VDRE VD and T3 together provided maximal gene activity. Our data suggest that the expression levels of VDRs, RXRs, RARs, and T3Rs and their specific ligands regulate the transcription of VD-responsive genes and illustrates the complexity of this interactive network of nuclear receptors.