title: Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice.
abstract: BACKGROUND
  In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia.
  
  
  METHODS
  A dominant-negative human EGFR mutant, which forms non-functional heterodimers with full-length endogenous EGFR, was successfully targeted to the parathyroid glands (PTGs) of FVB/N mice, using the 5' regulatory sequence of the PTH promoter. The parathyroid phenotype and serum chemistries of wild-type (WT) and transgenic mice were examined after 14 weeks of either sham operation or 75% renal mass reduction (NX).
  
  
  RESULTS
  Both genotypes had similar morphology and body weight, and NX-induction enhanced similarly serum blood urea nitrogen compared with sham-operated controls. However, despite similar serum calcium, phosphate and FGF23 levels in NX mice of both genotypes, parathyroid EGFR inactivation sufficed to completely prevent the marked increases in PTG enlargement, serum PTH and in parathyroid levels of transforming growth factor-α, a powerful EGFR-activator, and the VDR reductions observed in WT mice.
  
  
  CONCLUSIONS
  In CKD, parathyroid EGFR activation is essential for parathyroid hyperplasia and VDR loss, rendering this transgenic mouse a unique tool to scrutinize the pathogenesis of parathyroid and multiple organ dysfunction of CKD progression unrelated to parathyroid hyperplasia.
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, MO, USA Division of Experimental Nephrology, IRB Lleida, Lleida, Spain Renal Division, Hospital Universitari Arnau de Vilanova, Universidad de Lleida, Lleida, Spain.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Arcidiacono
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Experimental Nephrology, IRB Lleida, Lleida, Spain Renal Division, Hospital Universitari Arnau de Vilanova, Universidad de Lleida, Lleida, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, MO, USA Division of Experimental Nephrology, IRB Lleida, Lleida, Spain Renal Division, Hospital Universitari Arnau de Vilanova, Universidad de Lleida, Lleida, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology*; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D014511:Uremia / Q000150:complications*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D000089703:Fibroblast Growth Factor-23; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: calcium; phosphate; secondary hyperparathyroidism; transforming growth factor alpha; vitamin D receptor