Elevated serum levels of parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)2D3) or its less calcemic analogs). Enhanced TGFα/EGFR co-expression is the major mitogenic signal in uremic parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in parathyroid-TGFα/EGFR co-expression. In established hyperparathyroidism, characterized by highly enhanced-TGFα/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to parathyroid hyperplasia in humans. In advanced renal failure, reduced-parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of parathyroid growth arrest available at present.
|Number of pages||5|
|Journal||Journal of Steroid Biochemistry and Molecular Biology|
|State||Published - May 2004|
- Parathyroid hyperplasia
- Renal failure