Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor.
Journal - Journal of molecular endocrinology
Vitamin D compounds regulate PTH at the transcriptional level, presumably via binding to the vitamin D receptor (VDR), but the exact mechanism is presently unclear. We recently reported that the several vitamin D prohormones with low VDR affinity suppressed PTH, even when their activation was inhibited, raising the possibility that their actions may be VDR-independent. To test this hypothesis, we developed a novel organ culture that allowed the assessment of activities of the prohormones on PTH release from wild-type and VDR-null thyroparathyroid explants. The cultures remained viable with respect to PTH release for at least two weeks. Full suppression of PTH by the native vitamin D hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], required two days, consistent with a transcriptional mechanism, and was reversible, indicating that reduced PTH was not attributable to cell death. Inhibition of PTH release by 1,25(OH)2D3 and two prohormones, 25-hydroxyvitamin D3 and 1a-hydroxyvitamin D2 was observed in explants from wild-type mice but not in those from VDR null mice. These findings 1) are the first direct demonstration of the role of the VDR in regulation of PTH by 1,25(OH)2D3, 2) confirm that the suppressive actions of the vitamin D prohormones are mediated by the VDR, and 3) introduce a novel organ culture model that allows the ex vivo study of the function of parathyroid glands from transgenic animals.