title: EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease.
abstract: Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
authors.affiliation: Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Arcidiacono
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Sato
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Hernandez
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tominaga
authors.forename: Jorge
authors.initials: J
authors.lastname: Cannata-Andia
authors.forename: Eduardo
authors.initials: E
authors.lastname: Slatopolsky
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Dusso
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004351:Drug Resistance; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006965:Hyperplasia; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018167:Receptors, Calcitriol; D016211:Transforming Growth Factor alpha; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D002117:Calcitriol