title: The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.
abstract: BACKGROUND
  In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand.
  
  
  METHODS
  Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination.
  
  
  RESULTS
  While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%.
  
  
  CONCLUSIONS
  In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, MO, USA Division of Experimental Nephrology, IRB 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.
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000150:complications*; D010280:Parathyroid Glands / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D016211:Transforming Growth Factor alpha; D014815:Vitamins; D014807:Vitamin D; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat; D002117:Calcitriol
keywords: EGF receptor tyrosine kinase inhibitor; TGFα; transcriptional regulation; vitamin D receptor