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 |
Autori: | COZZOLINO, MARIO GENNARO (Secondo) |
Parole Chiave: | Parathyroid hyperplasia;TGFα; EGFR; Renal failure |
Settore Scientifico Disciplinare: | Settore MED/14 - Nefrologia |
Data di pubblicazione: | feb-2004 |
Rivista: | |
Tipologia: | Article (author) |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.jsbmb.2004.03.061 |
Appare nelle tipologie: | 01 - Articolo su periodico |
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