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.
1,25-Dihydroxyvitamin D downregulation of TGFα/EGFR expression and growth signaling: A mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure / A. Dusso, M. Cozzolino, Y. Lu, T. Sato, E. Slatopolsky. - In: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY. - ISSN 0960-0760. - 89-90(2004 Feb), pp. 507-511.
|Titolo:||1,25-Dihydroxyvitamin D downregulation of TGFα/EGFR expression and growth signaling: A mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure|
COZZOLINO, MARIO GENNARO (Secondo)
|Parole Chiave:||Parathyroid hyperplasia;TGFα; EGFR; Renal failure|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||feb-2004|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jsbmb.2004.03.061|
|Appare nelle tipologie:||01 - Articolo su periodico|