Cellular and molecular mechanisms of secondary hyperparathyroidism.

The objective of this review is to share important basic research insights into the mechanisms of secondary hyperparathyroidism. An understanding of these mechanisms is essential to more effectively treating the disease. Central underlying abnormalities are increased parathyroid hormone (PTH) gene expression and secretion, and parathyroid cell proliferation. Significant progress has been made in understanding these abnormalities at the cellular and molecular level, particularly their regulation. Studies point to a prominent role of calcium, phosphate and vitamin D as regulators of PTH and parathyroid cell proliferation. 1,25[OH]2 vitamin D3 decreases PTH synthesis and secretion. Small decreases in serum calcium and prolonged increases in serum phosphate as may occur in patients with chronic failure, increase PTH secretion, PTH gene expression, and parathyroid cell proliferation. Regulation at the level ofPTH gene expression is particularly significant given the limited amount of preformed mature PTH. It is now known that calcium and phosphate regulate PTH gene expression through changes in protective parathyroid cytosolic proteins that bind to an instability element in the PTH mRNA 3'-untranslated region and influence transcript stability. These findings may help guide the development of novel therapies for secondary hyperparathyroidism.