The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease

Nephrol Dial Transplant. 2015 Mar;30(3):423-33. doi: 10.1093/ndt/gfu311. Epub 2014 Oct 7.

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.

Keywords: EGF receptor tyrosine kinase inhibitor; TGFα; transcriptional regulation; vitamin D receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Calcitriol / pharmacology
  • Cell Proliferation
  • Cells, Cultured
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology
  • Gene Expression Regulation / drug effects*
  • Humans
  • Hyperparathyroidism, Secondary / drug therapy*
  • Hyperparathyroidism, Secondary / metabolism
  • Hyperparathyroidism, Secondary / pathology
  • Hyperplasia / etiology*
  • Hyperplasia / metabolism
  • Hyperplasia / 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
  • Transforming Growth Factor alpha / metabolism
  • Vitamin D / pharmacology*
  • Vitamins / pharmacology

Substances

  • 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