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dc.contributor.authorArcidiacono, Maria V.
dc.contributor.authorYang, Jing
dc.contributor.authorFernández i Giráldez, Elvira
dc.contributor.authorDusso Rosso, Adriana
dc.date.accessioned2018-04-30T10:29:42Z
dc.date.available2018-04-30T10:29:42Z
dc.date.issued2015-03-01
dc.identifier.issn0931-0509
dc.identifier.urihttp://hdl.handle.net/10459.1/63218
dc.description.abstractAbstract 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%. CONCLUSION: 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.
dc.description.sponsorshipThis work was supported by the following grants to A.D.: RO1 DK062713 from NIDDK; CEDAR (Center for D-receptor Activation Research); Abbott Pharmaceuticals, FIS PI11/00259 from Institutos de Salud Carlos III, Spanish Government and the Barnes Jewish Auxilary Chapter. The processing for serum chemistries was partly supported by Core C of the O’Brien Center for renal chemistries, Grant P30DK079333.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1093/ndt/gfu311
dc.relation.ispartofNephrology Dialysis Transplantation, 2015, vol. 30, num. 3, p. 423-433
dc.rights(c) Arcidiacono, Maria V. et al., 2015
dc.subjectEGF receptor tyrosine kinase inhibitor
dc.subjectTGFα
dc.subjectTranscriptional regulation
dc.subjectVitamin D receptor
dc.titleThe induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.
dc.title.alternativeADAM17 in parathyroid hyperplasia
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2018-04-30T10:29:42Z
dc.identifier.idgrec023298
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1093/ndt/gfu311


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