Babitt, J.L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539

Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Genetics (Impact Factor: 29.35). 06/2006; 38(5):531-9. DOI: 10.1038/ng1777
Source: PubMed


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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    • "Liver hepcidin is regulated primarily by the BMP/SMAD signaling pathway, which is considered the iron-dependent mechanism. Hemojuvelin (HJV) acts as a BMP co-receptors [7] and its activity is modulated by a liver-specific membrane protease, named TMPRSS6 [8]. BMP6 has been identified as the major physiological actor, although other BMPs or members of the TGF beta superfamily can induce hepcidin expression in vitro and in vivo. "
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    ABSTRACT: Hepcidin is a peptide hormone that controls systemic iron availability and is upregulated by iron and inflammation. Heparins have been shown to be efficient hepcidin inhibitors both in vitro and in vivo, even when their anticoagulant activity has been abolished by chemical reactions of oxidation/reduction (glycol-split). We analyzed a modified heparin type, characterized by a high, almost saturated, sulfation degree and low molecular weight. It inhibited hepcidin expression in hepatic HepG2 cells, and when used in mice, it readily suppressed liver hepcidin mRNA and serum hepcidin, with a significant decrease of spleen iron. This occurred also in inflammation-model, LPS-treated animals, and after heparin chronic ten-day treatments. The heparin had low/absent anticoagulant activity, as tested for factor-Xa and -IIA, APTT and anti Xa. It reduced triglyceride levels in the mice. This heparin acts faster and is more potent than the glycol split-heparins, probably because of its smaller molecular weight and higher sulfation degree. This modified heparin has potential applications for the treatment of diseases with high hepcidin levels.
    Biochemical Pharmacology 09/2014; 92(3). DOI:10.1016/j.bcp.2014.09.007 · 5.01 Impact Factor
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    • "The activated complex, in turn, phosphorylates Smad1,5,8/Smad4 complex, which then translocates to nucleus to modulate gene transcription (Wang et al., 2005; Babitt et al., 2006; Kautz et al., 2008). Hemojuvelin (HJV) acts as a coreceptor and is required to fully activate the BMP signaling ability (Babitt et al., 2006). The expression of BMP6 is proportional to hepatic iron concentrations and consistent with Hamp mRNA expression (Kautz et al., 2008). "
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    ABSTRACT: Matriptase-2, encoded by the TMPRSS6 gene, is a member of the type II transmembrane serine protease family. Matriptase-2 has structural and enzymatic similarities to matriptase-1, which has been implicated in cancer progression. Matriptase-2 was later established to be essential in iron homeostasis based on the phenotypes of iron-refractory iron deficiency anemia identified in mouse models as well as in human patients with TMPRSS6 mutations. TMPRSS6 is expressed mainly in the liver and negatively regulates the production of hepcidin, the systemic iron regulatory hormone. This review focuses on the current understanding of matriptase-2 biochemistry, and its role in iron metabolism and cancer progression. In light of recent investigations, the function of matriptase-2 in hepcidin regulation, how it is being regulated, as well as the therapeutic potential of matriptase-2 are also discussed.
    Frontiers in Pharmacology 05/2014; 5:114. DOI:10.3389/fphar.2014.00114 · 3.80 Impact Factor
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    • "HJV and other RGM family members function as BMP co-receptors that bind selectively to BMP ligands and receptors to enhance SMAD phosphorylation in response to BMP signals (Babitt et al., 2005, 2006; Samad et al., 2005). All RGMs share the ability to bind to the BMP2/BMP4 subfamily and enhance BMP2/BMP4 signaling (Babitt et al., 2005, 2006; Samad et al., 2005; Wu et al., 2012). "
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    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
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