Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
Jodie L. Babitt, … , Nancy C. Andrews, Herbert Y. Lin
Jodie L. Babitt, … , Nancy C. Andrews, Herbert Y. Lin
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1933-1939. https://doi.org/10.1172/JCI31342.
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Research Article

Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance

Abstract

Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been implicated in the pathogenesis of anemia of chronic disease, while hepcidin deficiency has a key role in the pathogenesis of the iron overload disorder hemochromatosis. We have recently shown that hemojuvelin is a coreceptor for bone morphogenetic protein (BMP) signaling and that BMP signaling positively regulates hepcidin expression in liver cells in vitro. Here we show that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores, and increases serum iron levels in vivo. These data support a role for modulators of the BMP signaling pathway in treating diseases of iron overload and anemia of chronic disease.

Authors

Jodie L. Babitt, Franklin W. Huang, Yin Xia, Yisrael Sidis, Nancy C. Andrews, Herbert Y. Lin

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Figure 3

Soluble HJV.Fc inhibits basal hepcidin expression and selectively inhibits BMP induction of hepcidin expression.

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Soluble HJV.Fc inhibits basal hepcidin expression and selectively inhibi...
(A) Western blot of purified soluble HJV.Fc fusion protein with anti-hemojuvelin antibody (α-HJV) and anti-Fc antibody (α-Fc). (B and C) HepG2 cells were incubated alone (control) or with 25 μg/ml HJV.Fc alone, 25 ng/ml BMP-2 alone, or a combination of HJV.Fc and BMP-2 as indicated. Total RNA was isolated and quantitative real-time RT-PCR for hepcidin mRNA relative to β-actin mRNA was performed as in Figure 1. Results are reported as the mean ± SD (n = 3 per group; *P = 0.03 for HJV.Fc compared with control; †P = 0.009 for HJV.Fc plus BMP-2 compared with BMP-2 alone). (D) Hep3B cells were transfected with the hepcidin promoter luciferase construct and pRL-TK. Transfected cells were incubated alone, with 5 ng/ml BMP-9, 50 ng/ml BMP-5, or 25 ng/ml BMP-2, BMP-4, BMP-6, or BMP-7 ligands, or with the BMP ligands plus 0.2 to 25 μg/ml HJV.Fc as indicated, followed by measurement of relative luciferase activity as in Figure 1. Results are reported as the mean ± SD of the percent decrease in relative luciferase activity for cells treated with BMP ligands in combination with HJV.Fc compared with cells treated with BMP ligands alone (n = 2 per group).