Low Intracellular Iron Increases the Stability of Matriptase-2

Zhao, Ningning; Nizzi, Christopher P.; Anderson, Sheila A.; Wang, Jiaohong; Ueno, Akikok; Tsukamoto, Hidekazu; Eisenstein, Richard S.; Enns, Caroline A.; Zhang, An-Sheng

doi:10.1074/jbc.m114.611913

Cited by 44 publications

(35 citation statements)

References 53 publications

(104 reference statements)

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“…We speculate that following EPO injection, the rapid erythropoiesis expansion may cause a transient drop of holo-transferrin and that transient iron deficiency can stabilize TMPRSS6/matriptase-2 on the cell surface. 38 Following matriptase-2 stabilization, the Bmp-Smad pathway is inhibited through the HjvBmp complex allowing a much more effective hepcidin inhibition by Erfe. Our data demonstrate that lack of Bmp-Smad signaling pathway inhibition prevents hepcidin suppression by Erfe.…”

Section: Discussionmentioning

confidence: 99%

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Nai

Rubio

Campanella

et al. 2016

Blood

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Key Points• Hyperactivation of the BMP-SMAD pathway blunts EPO-mediated hepcidin inhibition.• Lack of BMP-SMAD pathway inhibition by matriptase-2 abrogates the ERFEmediated hepcidin suppression in response to EPO.Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the

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Section: Discussionmentioning

confidence: 99%

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Nai

Rubio

Campanella

et al. 2016

Blood

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“…This is likely a common mechanism of the EPO effect: In this way, the degree of iron saturation of transferrin (that is influenced by bone marrow activity) influences also hepcidin activation in a homeostatic manner (Figure ). Loss of TFR2 and likely increased activity of TMPRSS6 (less degraded in iron deficiency) reduce BMP/SMAD pathway activation allowing ERFE to function . Further studies will elucidate the molecular pathway in detail.…”

Section: The Inverse Relationshipmentioning

confidence: 99%

The mutual control of iron and erythropoiesis

Camaschella

Pagani

Nai

et al. 2016

Int J Lab Hematology

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Summary Background Iron is essential for hemoglobin synthesis during terminal erythropoiesis. To supply adequate iron the carrier transferrin is required together with transferrin receptor endosomal cycle and normal mitochondrial iron utilization. Iron and iron protein deficiencies result in different types of anemia. Iron‐deficiency anemia is the commonest anemia worldwide due to increased requirements, malnutrition, chronic blood losses and malabsorption. Mutations of transferrin, transferrin receptor cycle proteins, enzymes of the first step of heme synthesis and iron sulfur cluster biogenesis lead to rare anemias, usually accompanied by iron overload. Hepcidin plays an indirect role in erythropoiesis by controlling plasma iron. Inappropriately high hepcidin levels characterize the rare genetic iron‐refractory iron‐deficiency anemia (IRIDA) and the common anemia of chronic disease. Iron modulates both effective and ineffective erythropoiesis: iron restriction reduces heme and alpha‐globin synthesis that may be of benefit in thalassemia. Material and Methods This review relies on the analysis of the most recent literature and personal data. Results Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and EPO treatment. Erythroferrone, produced by EPO‐stimulated erythropoiesis, inhibits hepcidin only when the activity of BMP/SMAD pathway is low, suggesting that EPO somehow modulates the latter signaling. Erythroblasts sense circulating iron through the second transferrin receptor (TFR2) that, in animal models, modulates the sensitivity of the erythroid cells to EPO. Discussion The advanced knowledge of the regulation of systemic iron homeostasis and erythropoiesis‐mediated hepcidin regulation is leading to the development of targeted therapies for anemias and iron disorders.

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“…Furthermore, iron chelators have been reported to increase hepatic hepcidin expression [11,12]. Importantly, increased hepcidin expression reduces iron overload and improves anemia effectively [13,14].…”

Section: Introductionmentioning

confidence: 99%

Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

Upanan

Pangjit

Uthaipibull

et al. 2015

Asian Pacific Journal of Tropical Biomedicine

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A B S T R A C T Objective:To evaluate the efficacy of deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) or green tea extract (GTE) in enhancing expression of hepatic hepcidin1 (Hamp1) mRNA and relieving iron overload in β-globin knockout thalassemic mice. Methods:The β-globin knockout thalassemic mice were fed with a ferrocene-supplemented diet for 2 months and oral administration of deionized water, DFP (50 mg/kg), CM1 (50 mg/kg), GTE (50 mg epigallocatechin 3-gallate equivalent/kg), GTE along with DFP (50 mg/kg), and GTE along with CM1 (50 mg/kg) every day for 3 months. Levels of hepatic Hamp1 mRNA, plasma non-transferrin bound iron, plasma alanine aminotransferase activity and tissue iron content were determined.Results: All chelation treatments could reduce plasma non-transferrin bound iron concentrations. Additionally, hepatic Hamp1 mRNA expression was significantly up-regulated in the mice in a GTE + DFP combined treatment, correlating with a decrease in the plasma alanine aminotransferase activity and tissue iron deposition. Conclusions:The GTE + DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent β-thalassemic mice, by chelating toxic iron in plasma and tissues, and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen. There is probably an advantage in giving GTE with DFP when treating patients with iron overload.

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Low Intracellular Iron Increases the Stability of Matriptase-2

Cited by 44 publications

References 53 publications

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

The mutual control of iron and erythropoiesis

Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

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