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.
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.
Dusso
Adriana
A
Renal Division, Washington University School of Medicine, Campus Box 8126, 660 S. Euclid Ave., St. Louis, MO 63110, USA. adusso@im.wustl.edu
Cozzolino
Mario
M
Lu
Yan
Y
Sato
Tetsuhiko
T
Slatopolsky
Eduardo
E
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*
D016211:Transforming Growth Factor alpha; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D066246:ErbB Receptors