All patients in end-stage renal failure develop secondary hyperparathyroidism, a stat characterized by enlarged parathyroid glands and high serum levels of parathyroid hormone (PTH). The resulting disruption of mineral homeostasis leads to severe bone disorders including osteitis fibrosa. Consequently, a fundamental clinical goal is to control the synthesis and/or secretion of PTH in these patients. In this regard, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which decreases transcription of the PTH gene, is used to treat this disorder. Recent data suggest that retinoid X receptors (RXRs), one class of nuclear receptors that mediate vitamin A action, are involved i vitamin D- controlled transcription, suggesting that vitamins A and D may coordinately regulate PTH expression. Presently, the roles of vitamin A and the retinoid receptors in the parathyroid gland or in PTH expression are unknown. Therefore, the overall goal is this proposal is to determine whether vitamin A and the retinoid receptors, either alone or in concerted action with 1,25(OH)2D3, affect the expression of PTH in normal and in renal disease states. Preliminary data supporting this hypothesis show that 9-cis retinoic acid suppresses the secretion of PTH in parathyroid cell culture. This proposal examines: 1) the parathyroid gland as a vitamin A responsive tissue; 2) the in vivo effect of retinoids on PTH expression in the normal, in the vitamin A deficient, and in the hyperparathyroid rat; 30 the mechanism through which retinoic acid suppresses PTH secretion in culture; and 4) the effect of retinoids and their nuclear receptors on vitamin D-mediated suppression of PTH gene transcription. Specially, expression of nuclear receptors and cellular binding proteins for retinoids will be examined in the parathyroid gland. In vivo experiments will measure the effect of vitamin A administration on serum PTH and preprolPTH mRNA. Bovine parathyroid cell culture will determine the mechanism of retinoic acid-mediated PTH suppression. Finally, transient gene expression studies will delineate the molecular mechanism through which retinoids suppress PTH and will test if retinoids and/or their nuclear receptors affect 1,25(OH)2D3-mediated PTH expression. The results of these studies may have direct clinical relevance to the development of more efficacious treatments of secondary hyperparathyroidism in chronic renal failure.
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