Erythroferrone and matriptase‐2 independently regulate hepcidin expression

Aschemeyer, Sharraya; Gabayan, Victoria; Ganz, Tomas; Nemeth, Elizabeta; Kautz, Léon

doi:10.1002/ajh.24672

Cited by 27 publications

(21 citation statements)

References 6 publications

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“…Bitopertin reduces liver iron overload and oxidative stress and modulates liver hepcidin expression in a dose-dependent manner. Liver iron overload is a distinguishing feature of β-thal, a consequence of ineffective erythropoiesis and inappropriate hepcidin (Hamp) downregulation (28)(29)(30). In Hbb th3/+ mice, bitopertin treatment (30 mg/kg/d) significantly reduced liver iron overload in both hepatocytes and Kupffer cells compared with vehicle-treated animals ( Figure 3A and Supplemental Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Federti¹,

Winter²,

Koerner³

et al. 2019

JCI Insight

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Section: Resultsmentioning

confidence: 99%

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Federti¹,

Winter²,

Koerner³

et al. 2019

JCI Insight

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“…Although it has been proposed that Tmprss6 mediates the liver pSmad1/5 reduction in response to EPO required for hepcidin suppression, 45 a recent correspondence reported that erythroferrone still suppressed Hamp and Id1 mRNA in Tmprss6 2/2 primary hepatocytes, 56 suggesting a Tmprss6-independent effect. Future studies will be needed to understand the molecular mechanisms by which erythroferrone suppresses Smad1/5 signaling and the full details of crosstalk between these pathways.…”

Section: Discussionmentioning

confidence: 99%

Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice

Wang

Core

Canali

et al. 2017

Blood

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Anemia suppresses liver hepcidin expression to supply adequate iron for erythropoiesis. Erythroferrone mediates hepcidin suppression by anemia, but its mechanism of action remains uncertain. The bone morphogenetic protein (BMP)-SMAD signaling pathway has a central role in hepcidin transcriptional regulation. Here, we explored the contribution of individual receptor-activated SMADs in hepcidin regulation and their involvement in erythroferrone suppression of hepcidin. In Hep3B cells, or but not knockdown inhibited hepcidin () messenger RNA (mRNA) expression. Hepatocyte-specific double-knockout mice exhibited ∼90% transferrin saturation and massive liver iron overload, whereas mice or female mice with 1 functional or allele had modestly increased serum and liver iron, and single-knockout or mice had minimal to no iron loading, suggesting a gene dosage effect. mRNA was reduced in all Cre mouse livers at 12 days and in all Cre primary hepatocytes. However, only double-knockout mice continued to exhibit low liver at 8 weeks and failed to induce in response to Bmp6 in primary hepatocyte cultures. Epoetin alfa (EPO) robustly induced bone marrow erythroferrone () mRNA in control and mice but suppressed hepcidin only in control mice. Likewise, erythroferrone failed to decrease mRNA in primary hepatocytes and/ knockdown Hep3B cells. EPO and erythroferrone reduced liver Smad1/5 phosphorylation in parallel with mRNA in control mice and Hep3B cells. Thus, and have overlapping functions to govern hepcidin transcription. Moreover, erythropoietin and erythroferrone target Smad1/5 signaling and require Smad1/5 to suppress hepcidin expression.

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“…Strong support for this proposal comes from the observation that the hemojuvelin (HJV)-dependent signaling pathway is upregulated in Tmprss6 -mutated mice [ 24 , 25 ]; on the other hand, no direct in vivo evidence for TMPRSS6-mediated HJV cleavage has yet been obtained [ 26 ]. Alternatively, since the downregulation of Hamp expression by EPO requires both functional TMPRSS6 and functional ERFE, it is theoretically possible that both proteins operate in the same pathway and that the proteolytic activity of TMPRSS6 modulates ERFE function [ 27 ]; however, recent evidence argues against this hypothesis, since recombinant ERFE is able to downregulate Hamp in hepatocytes isolated from Tmprss6-/- mice [ 28 ]. At the protein level, it has already been shown that plasma ERFE levels are increased in Tmprss6 -/- mice in comparison with wild-type mice [ 28 ]; no data regarding the effect of EPO on ERFE protein synthesis in Tmprss6 -mutated mice have so far been published.…”

Section: Introductionmentioning

confidence: 99%

Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice

et al. 2017

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Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.

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Erythroferrone and matriptase‐2 independently regulate hepcidin expression

Cited by 27 publications

References 6 publications

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice

Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice

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