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%.

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.

• Authors: Maria Vittoria Arcidiacono, Jing Yang, Elvira Fernandez, Adriana Dusso
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 30 Issue 3 Pg. 423-33 (Mar 2015) ISSN: 1460-2385 [Electronic] England
• PMID: 25294851 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Antineoplastic Agents
• CCAAT-Enhancer-Binding Protein-beta
• Parathyroid Hormone
• RNA, Messenger
• Receptors, Calcitriol
• Transforming Growth Factor alpha
• Vitamins
• Vitamin D
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human
• Adam17 protein, rat
• Calcitriol

Topics

• ADAM Proteins (antagonists & inhibitors, genetics, metabolism)
• ADAM17 Protein
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Blotting, Western
• CCAAT-Enhancer-Binding Protein-beta (genetics, metabolism)
• Calcitriol (pharmacology)
• Cell Proliferation
• Cells, Cultured
• ErbB Receptors (genetics, metabolism)
• Erlotinib Hydrochloride (pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• Hyperparathyroidism, Secondary (drug therapy, metabolism, pathology)
• Hyperplasia (etiology, metabolism, pathology)
• Immunoenzyme Techniques
• Kidney Diseases (complications)
• Parathyroid Glands (drug effects)
• Parathyroid Hormone (metabolism)
• RNA, Messenger (genetics)
• Rats
• Real-Time Polymerase Chain Reaction
• Receptors, Calcitriol (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor alpha (genetics, metabolism)
• Vitamin D (pharmacology)
• Vitamins (pharmacology)