Regulation of the parathyroid hormone gene by vitamin D, calcium and phosphate

Secondary hyperparathyroidism is a frequent complication of chronic renal f ailure resulting in severe bone disease. Secondary hyperparathyroidism is c om posed of increased in parathyroid hormone (PTH) synthesis and secretion due to an increase in PTH gene expression and parathyroid cell proliferatio n. PTH gene expression is regulated by calcium, phosphate and 1,25-dihydrox y vitamin D (1,25(OH)(2)D). 1,25(OH)(2)D-3 injected to rats leads to a dram atic decrease in PTH gene transcription without any increase in serum calci um. Hypocalcemia leads to a large increase in PTH mRNA levels which is post -transcriptional. Hypophosphatemia leads to a marked decrease in PTH gene e xpression that is also post-transcriptional. The mechanisms of the post-tra nscriptional effects of calcium and phosphate on the PTH gene have shown to be due to changes in protein-RNA interactions at the PTH mRNA 3'-UTR. Hypo calcemia leads to increased binding of parathyroid cytosolic proteins to th e PTH mRNA 3'-UTR and hypophosphatemia to decreased binding of these protei ns to the PTH mRNA 3'-UTR. The binding of the parathyroid proteins stabiliz es the PTH RNA in an in vitro degradation assay. In rats with experimental uremia due to 5/6 nephrectomy, there is an increase in PTH mRNA levels due to a decrease in degradation of the PTH RNA as determined by this assay. Th e characterization of the parathyroid cytosolic proteins that interact with the PTH mRNA 3'-UTR may lead to a clearer understanding of how changes in serum calcium and phosphate result in secondary hyperparathyroidism.