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)(2)D(3)) or its less calcemic analogs). Enhanced
TGFalpha/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-
TGFalpha/EGFR co-expression. In established
hyperparathyroidism, characterized by highly enhanced-
TGFalpha/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.