25-Hydroxyvitamin D3 suppresses PTH synthesis and secretion by bovine parathyroid cells

摘要

Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Recently, human parathyroid glands have been shown to express 25-hydroxyvitamin D 1-hydroxylase (1OHase), but documentation of the 1OHase activity in parathyroid cells and its potential role in activating 25-hydroxyvitamin D3 (25(OH)D3) to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) have not been reported. The relative potencies of 25(OH)D3 and 1,25(OH)2D3 in reducing PTH secretion and mRNA were determined in primary cultures of bovine parathyroid cells (bPTC). The effects of blocking 1OHase activity on suppression of PTH mRNA and induction of 24-hydroxylase mRNA were examined. Vitamin D receptor (VDR) affinities were estimated by intact cell competitive binding assay. Metabolism of 25(OH)D3 by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D3 suppressed PTH secretion and mRNA (ED50=2nM), but was several hundred times less potent than 1,25(OH)2D3. The lower potency of 25(OH)D3 correlated with its lower VDR affinity. bPTCs converted 25(OH)D3 to 1-hydroxylated metabolites, but the rate of conversion was low. Inhibition of 1OHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D3-mediated suppression of PTH. Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D3. In conclusion, 25(OH)D3 suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR.