title: 1,25-Dihydroxyvitamin D downregulation of TGFalpha/EGFR expression and growth signaling: a mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure.
abstract: 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.
authors.affiliation: Renal Division, Washington University School of Medicine, Campus Box 8126, 660 S. Euclid Ave., St. Louis, MO 63110, USA. adusso@im.wustl.edu
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
authors.forename: Mario
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Sato
authors.forename: Eduardo
authors.initials: E
authors.lastname: Slatopolsky
mesh_terms: D002455:Cell Division / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia; D010280:Parathyroid Glands / Q000473:pathology*; D051437:Renal Insufficiency / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000502:physiology*
chemical_list: D016211:Transforming Growth Factor alpha; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D066246:ErbB Receptors