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Babitt, J. L. et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939

Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 08/2007; 117(7):1933-9. DOI: 10.1172/JCI31342
Source: PubMed

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.

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    • "Hepcidin negatively regulates cellular iron export by promoting the degradation of ferroportin (Nemeth et al., 2004), the only known iron exporter present on the surface of duodenal enterocytes, macrophages, and hepatocytes and thus limits iron absorption and iron release. It is now well established that Hamp expression is regulated by the bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) signaling pathway (Babitt et al., 2006, 2007). "
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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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    • "Multiple mechanisms have been proposed for endogenous sHJV generation, including cleavage by the pro-protein convertase furin and the type II transmembrane serine protease TMPRSS6 (Kuninger et al., 2008; Lin et al., 2008; Silvestri et al., 2008a,b). Whereas membrane HJV is a co-receptor for the BMP signaling complex (Babitt et al., 2006), sHJV can antagonize BMP signaling, presumably by binding and sequestering BMP ligands from interacting with cell-surface BMP type I and type II receptors (Babitt et al., 2007) (Figure 1). Indeed, the relative binding affinity of HJV for various BMP ligands roughly correlated with the ability of sHJV to inhibit their biological activity (Babitt et al., 2007; 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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    • "When present in the membrane-bound form, HJV serves as a coreceptor for bone morphogenetic proteins, particularly BMP6, and induces hepcidin expression via phosphorylation of Smads 1/5/8 [12,13]. The soluble form of HJV traps BMPs by binding to them, and consequently blocks BMP signaling, phosphorylation of Smads, and transcription of HAMP [10,14]. IL-6 induces HAMP transcription through phosphorylation of STAT3 [15]; this activity is responsible for elevation of circulating levels of hepcidin during inflammation, causing inflammation-associated anemia [16]. "
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    ABSTRACT: Matriptase-2 (also known as TMPRSS6) is a critical regulator of the iron-regulatory hormone hepcidin in the liver; matriptase-2 cleaves membrane-bound hemojuvelin and consequently alters bone morphogenetic protein (BMP) signaling. Hemojuvelin and hepcidin are expressed in the retina and play a critical role in retinal iron homeostasis. However, no information on the expression and function of matriptase-2 in the retina is available. The purpose of the present study was to examine the retinal expression of matriptase-2 and its role in retinal iron homeostasis. RT-PCR, quantitative PCR (qPCR), and immunofluorescence were used to analyze the expression of matriptase-2 and other iron-regulatory proteins in the mouse retina. Polarized localization of matriptase-2 in the RPE was evaluated using markers for the apical and basolateral membranes. Morphometric analysis of retinas from wild-type and matriptase-2 knockout (Tmprss6(msk/msk) ) mice was also performed. Retinal iron status in Tmprss6(msk/msk) mice was evaluated by comparing the expression levels of ferritin and transferrin receptor 1 between wild-type and knockout mice. BMP signaling was monitored by the phosphorylation status of Smads1/5/8 and expression levels of Id1 while interleukin-6 signaling was monitored by the phosphorylation status of STAT3. Matriptase-2 is expressed in the mouse retina with expression detectable in all retinal cell types. Expression of matriptase-2 is restricted to the apical membrane in the RPE where hemojuvelin, the substrate for matriptase-2, is also present. There is no marked difference in retinal morphology between wild-type mice and Tmprss6(msk/msk) mice, except minor differences in specific retinal layers. The knockout mouse retina is iron-deficient, demonstrable by downregulation of the iron-storage protein ferritin and upregulation of transferrin receptor 1 involved in iron uptake. Hepcidin is upregulated in Tmprss6(msk/msk) mouse retinas, particularly in the neural retina. BMP signaling is downregulated while interleukin-6 signaling is upregulated in Tmprss6(msk/msk) mouse retinas, suggesting that the upregulaton of hepcidin in knockout mouse retinas occurs through interleukin-6 signaling and not through BMP signaling. The iron-regulatory serine protease matriptase-2 is expressed in the retina, and absence of this enzyme leads to iron deficiency and increased expression of hemojuvelin and hepcidin in the retina. The upregulation of hepcidin expression in Tmprss6(msk/msk) mouse retinas does not occur via BMP signaling but likely via the proinflammatory cytokine interleukin-6. We conclude that matriptase-2 is a critical participant in retinal iron homeostasis.
    Molecular vision 04/2014; 20:561-574. · 2.25 Impact Factor
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