Article

Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.

Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Genetics (Impact Factor: 29.65). 06/2006; 38(5):531-9. DOI: 10.1038/ng1777
Source: PubMed

ABSTRACT Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.

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    ABSTRACT: Aims: Hereditary hemochromatosis (HH) is an iron overload disease that is caused by mutations in HFE, HJV, and several other genes. However, whether HFE-HH and HJV-HH share a common pathway via hepcidin regulation is currently unclear. Recently, some HH patients have been reported to carry concurrent mutations in both the HFE and HJV genes. To dissect the roles and molecular mechanisms of HFE and/or HJV in the pathogenesis of HH, we studied Hfe-/-, Hjv-/-, and Hfe-/-Hjv-/- double-knockout mouse models. Results: Hfe-/-Hjv-/- mice developed iron overload in multiple organs at levels comparable to Hjv-/- mice. Following an acute delivery of iron, the expression of hepcidin (i.e., Hamp1 mRNA) was increased in the livers of wild-type and Hfe-/- mice, but not in either Hjv-/- or Hfe-/-Hjv-/- mice. Furthermore, iron-induced phosphorylation of Smad1/5/8 was not detected in the livers of Hjv-/- or Hfe-/-Hjv-/- mice. Innovation: We generated and phenotypically characterized Hfe-/-Hjv-/- double-knockout mice. In addition, because they faithfully phenocopy clinical HH patients, these mouse models are an invaluable tool for mechanistically dissecting how HFE and HJV regulate hepcidin expression. Conclusions: Based on our results, we conclude that HFE may depend on HJV for transferrin-dependent hepcidin regulation. The presence of residual hepcidin in the absence of HFE suggests either the presence of an unknown regulator (for example, TFR2) that is synergistic with HJV or that HJV is sufficient to maintain basal levels of hepcidin.

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