Predominant role of 250HD in the negative regulation of PTH expression: Clinical relevance for hypovitaminosis D

Although severe deficiency of bioactive vitamin D (1,2501-121)) causes rickets, mild insufficiency of the hormone, known as hypovitammosis D, is responsible for the occurrence of secondary hyperparathyroidism and osteoporosis. To clarify the pathophysiology of the disease, we studied the negative feedback effect of 1,25OH2D and its precursor 25OHD on the transcriptional activity of parathyroid hormone (PTH) gene using the PT-r parathyroid cell line. We found that PT-r cells express endogenous I (x-hydroxylase as well as PTH mRNAs. We also found the potent suppressive effect of physiological concentration of 25OHD on the transcriptional activity of PTH gene. A similar effect was obtained with 1,250H2D but only with pharmacological concentration. Interestingly, the effect of 25OHD was completely abolished when the cells were treated with 1 alpha-hydroxylase inhibitor ketoconazole. These results suggest that the negative feedback regulation of vitamin D on PTH gene transcription occurs not by the end-product 1,250H2D but by its prohormone 25OHD via intracellular activation by 1 alpha-hydroxylase within the parathyroid cells. (c) 2008 Elsevier Inc. All rights reserved.