Hepcidin treatment in <i>Hfe</i><sup>−/−</sup> mice diminishes plasma iron without affecting erythropoiesis

Morán-Jiménez, María-Josefa; Méndez, Manuel; Santiago, Begoña; Rodríguez‐García, María Elena; Moreno-Carralero, María-Isabel; Sánchez-Lucío, Ana-Cristina; Grau, Montserrat; Enríquez-de-Salamanca, Rafael

doi:10.1111/j.1365-2362.2010.02291.x

Cited by 20 publications

(13 citation statements)

References 28 publications

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“…by guest www.bloodjournal.org From with synthetic hepcidin (50 g every 2 days for 2 months starting a 8 weeks of age) produced a significant reduction (24%) in plasma iron concentration compared with treatment with saline alone, but did not alter hepatic or splenic iron stores. 43 It is difficult to compare these published effects of BMP6 and hepcidin administration directly to the effects of genetic disruption of Tmprss6 because in the Hfe Ϫ/Ϫ mice we studied, Tmprss6 function was deficient since birth. In future studies, alternative genetic approaches, such as inducible gene targeting or siRNA gene knockdown, might be used to determine whether iron loading in Hfe Ϫ/Ϫ mice can be reduced if Tmprss6 inhibition is initiated at a later age.…”

Section: Discussionmentioning

confidence: 99%

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Finberg¹,

Whittlesey²,

Andrews

2011

Blood

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The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe ؊/؊ mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/ Smad target genes. IntroductionHereditary hemochromatosis associated with HFE mutation (HFE-HH) is a disorder of variable penetrance in which excessive absorption of dietary iron causes iron to accumulate in tissues; in some cases, cellular damage caused by iron leads to organ failure. HFE-HH is characterized by insufficient expression of hepcidin, a circulating peptide hormone produced by the liver in response to several physiologic stimuli, including iron loading. Hepcidin inhibits the absorption of dietary iron and the release of iron from macrophage stores by triggering the internalization and degradation of ferroportin, a cellular iron exporter present on the basolateral membrane of enterocytes and the plasma membrane of macrophages. 1 Both patients with HFE-HH and Hfe knockout (Hfe Ϫ/Ϫ ) mice exhibit hepcidin expression that is inappropriately low relative to their elevated body iron stores, explaining their excessive uptake of dietary iron. [2][3][4] The hepcidin insufficiency in HFE-HH leads to a characteristic distribution of iron stores that is primarily hepatocellular and shows relative sparing of reticuloendothelial cells. [5][6][7] Hepatic expression of a hepcidin transgene was found to inhibit iron accumulation in Hfe Ϫ/Ϫ mice, 3 demonstrating that hepcidin insufficiency is central to the pathogenesis of HFE-HH.The mechanism by which HFE promotes hepcidin expression is not fully understood. HFE, which shares structural homology with major histocompatibility complex class I molecules, heterodimerizes with ␤2-microglobulin. 8 Studies in mouse models suggest that Hfe, which competes with transferrin for binding to transferrin receptor 1 (Tfr1), 9 induces hepcidin expression when dissociated from Tfr1. 10 In vitro studies suggest that interaction of HFE with TFR2, a homolog of TFR1, is also necessary for the induction of hepcidin expression by iron-loaded transferrin. 11 Selective disruption of Hfe in hepatocytes causes hepatic iron overload and hepcidin suppression, indicating that Hfe promotes hepcidin expression in hepatocytes. 12 The bone morphogenetic protein (BMP)/SMAD signaling pathway is a key pathway promoting hepcidin transcription by hepatocytes. Binding of BMPs, members of the transformi...

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Section: Discussionmentioning

confidence: 99%

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Finberg¹,

Whittlesey²,

Andrews

2011

Blood

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“…There are several sources of experimental support for this hypothesis. In one investigation, intraperitoneal injection of Hamp resulted in decreased plasma iron levels in a mouse model of hemochromatosis (Hfe -/-) [14]. In another study, transgenic Hamp expression in adult Hfe -/-mice with established iron overload was sufficient to cause a redistribution of iron in the liver and spleen from parenchymal cells to Kupffer cells and splenic macrophages, respectively [15].…”

mentioning

confidence: 99%

Prospects for a hepcidin mimic to treat β-thalassemia and hemochromatosis

Parrow

Gardenghi

Rivella³

2011

Expert Review of Hematology

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“…As Tregs require IL-2 for their survival and function but do not produce it, it was thought that Teffs would be important providers of IL-2 to Tregs. In vivo mixing experiments with IL-2-deficient and -sufficient Tregs and Teffs confirmed this IL-2-based interdependence of Tregs and Teffs and led to the suggestion that Teffs were required to help maintain a functional Treg compartment (7,8). Other studies provided additional support for the existence of a feedback loop between Tregs and Teffs, a loop that is important for preventing autoimmune and lymphoproliferative disease (9)(10)(11).…”

Section: Tregs Depend On Teffsmentioning

confidence: 87%

“…Despite the precedents in the literature (7)(8)(9)(10)(11), few reports of the influence of Teffs on Tregs are as clear and informative as the one presented by Grinberg-Bleyer et al in this issue of the JCI (6). In their study, the authors investigated the effect of Teffs on Tregs using mouse models of autoimmune diabetes.…”

Section: A Feedback Loop Between Tregs and Teffs In Type 1 Diabetesmentioning

confidence: 99%

A tincture of hepcidin cures all: the potential for hepcidin therapeutics

Bartnikas

Fleming²

2010

J. Clin. Invest.

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Hepcidin treatment in Hfe^−/− mice diminishes plasma iron without affecting erythropoiesis

Abstract: Treatment with sustained doses of hepcidin diminishes plasma iron concentrations in Hfe(-/-) mice.

Cited by 20 publications

References 28 publications

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Prospects for a hepcidin mimic to treat β-thalassemia and hemochromatosis

A tincture of hepcidin cures all: the potential for hepcidin therapeutics

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Hepcidin treatment in Hfe−/− mice diminishes plasma iron without affecting erythropoiesis

Abstract: Treatment with sustained doses of hepcidin diminishes plasma iron concentrations in Hfe(-/-) mice.

Cited by 20 publications

References 28 publications

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Prospects for a hepcidin mimic to treat β-thalassemia and hemochromatosis

A tincture of hepcidin cures all: the potential for hepcidin therapeutics

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Hepcidin treatment in Hfe^−/− mice diminishes plasma iron without affecting erythropoiesis