The induction of C/EBP' 2 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- (TGF) 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 TGF, the most potent EGFR-activating ligand. Methods Computer analysis of the ADAM17 promoter identified TGF and C/EBP' 2 as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGF /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 TGF signals, active vitamin D to induce C/EBP' 2 or the combination. Results While TGF induced ADAM17-promoter activity by 2.2-fold exacerbating TGF /EGFR-driven growth, ectopic C/EBP' 2 expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGF and inversely with C/EBP' 2. Furthermore, combined erlotinib + calcitriol treatment suppressed TGF /EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBP' 2 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/EBP' 2 to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. Conclusion In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBP' 2 to efficaciously attenuate the severe ADAM17/TGF synergy, which drives PTG enlargement and high PTH.