Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice

Authors

  • Elena Corradini,

    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
    2. Laboratory of Hereditary and Metabolic Diseases of the Liver, “Mario Coppo” Liver Research Center, University Hospital of Modena and Reggio Emilia, Modena, Italy
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    • Potential conflict of interest: J.L.B. has ownership interest in a start-up company Ferrumax Pharmaceuticals, which has licensed technology from the Massachusetts General Hospital based on her work.

  • Delphine Meynard,

    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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  • Qifang Wu,

    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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  • Shan Chen,

    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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  • Paolo Ventura,

    1. Laboratory of Hereditary and Metabolic Diseases of the Liver, “Mario Coppo” Liver Research Center, University Hospital of Modena and Reggio Emilia, Modena, Italy
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  • Antonello Pietrangelo,

    1. Laboratory of Hereditary and Metabolic Diseases of the Liver, “Mario Coppo” Liver Research Center, University Hospital of Modena and Reggio Emilia, Modena, Italy
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  • Jodie L. Babitt

    Corresponding author
    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
    • Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St., CPZN-8216, Boston, MA 02114
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    • fax (617) 643-3182


  • E.C. was supported in part by a Tosteson Postdoctoral Fellowship Awards from the Massachusetts Biomedical Research Corporation (MBRC) at Massachusetts General Hospital. P.V. and A.P. were supported in part by PRIN '08 grant and Telethon GGP10233 grant. J.L.B. was supported in part by NIH grants K08 DK075846 and RO1 DK087727, and by a Claflin Distinguished Scholar Award from the Massachusetts General Hospital.

  • See Editorial on Page 16

Abstract

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo. (HEPATOLOGY 2011;)

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