Erythroferrone Inhibits the Induction of Hepcidin By BMP6

Arezes, João; Foy, Niall; McHugh, Kirsty; Sawant, Anagha; Benard, Susan; Quinkert, Doris; Terraube, Virginie; Brinth, Alette; Tam, May; LaVallie, Edward R.; Taylor, Stephen; Armitage, Andrew E.; Pasricha, Sant‐Rayn; Cunningham, Orla; Lambert, Matthew; Draper, Simon J.; Jasuja, Reema; Drakesmith, Alexander

doi:10.1182/blood-2018-99-111140

Cited by 23 publications

(47 citation statements)

References 9 publications

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“…Figure S6). Erfe has been shown to suppress BMP/SMAD signaling in vivo and in vitro and to inhibit hepcidin induction by BMP6 (78). Thus our data suggest that cFGF23 decreases hepcidin induction by LPS by increasing Erfe, and possibly suppressing the BMP6/SMAD pathway.…”

Section: Discussionsupporting

confidence: 54%

C-FGF23 peptide alleviates hypoferremia during acute inflammation

Agoro¹,

Park²,

Hénaff³

et al. 2020

haematol

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Hypoferremia results as an acute phase response to infection and inflammation aiming to reduce iron availability to pathogens. Activation of toll-like receptors (TLRs), the key sensors of the innate immune system, induces hypoferremia mainly through the rise of the iron hormone hepcidin. Conversely, stimulation of erythropoiesis suppresses hepcidin expression via induction of the erythropoietin-responsive hormone erythroferrone. Iron deficiency stimulates transcription of the osteocyte-secreted protein FGF23. Here we hypothesized that induction of FGF23 in response to TLR4 activation is a potent contributor to hypoferremia and, thus, impairment of its activity may alleviate hypoferremia induced by lipopolysaccharide (LPS), a TLR 4 agonist. We used the C-terminal tail of FGF23 to impair endogenous full-length FGF23 signaling in wild-type mice, and investigated its impact on hypoferremia. Our data show that FGF23 is induced as early as pro-inflammatory cytokines in response to LPS, followed by upregulation of hepcidin and downregulation of erythropoietin (Epo) expression in addition to decreased serum iron and transferrin saturation. Further, LPS-induced hepatic and circulating hepcidin were significantly reduced by FGF23 signaling disruption. Accordingly, iron sequestration in liver and spleen caused by TLR4 activation was completely abrogated by FGF23 signaling inhibition, resulting in alleviation of serum iron and transferrin saturation deficit.Taken together, our studies highlight for the first time that inhibition of FGF23 signaling alleviates LPS-induced acute hypoferremia.

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Section: Discussionsupporting

confidence: 54%

C-FGF23 peptide alleviates hypoferremia during acute inflammation

Agoro¹,

Park²,

Hénaff³

et al. 2020

haematol

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“…Recent evidence indicates that ERFE inhibits hepcidin expression by antagonizing select members of the bone morphogenetic protein (BMP) family (Arezes et al, 2018;Wang et al, 2020). BMP signaling in hepatocytes regulates hepcidin transcription in response to plasma iron concentrations and hepatic iron stores, and the pathological loss of BMP signaling causes hepcidin deficiency and systemic iron overload (Canali et al, 2017;Koch et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, BMP2 and 6 secreted by the sinusoidal endothelial cells in the liver are the key regulators of hepcidin transcription (Wang et al, 2020). ERFE lowers hepcidin transcription by sequestering the BMP2/6 heterodimer (Wang et al, 2020), but ERFE was also reported to bind other BMPs including BMP2, 4, 5, 6 and 7 (Arezes et al, 2020a;Arezes et al, 2018). Considering that BMP signaling has pleiotropic effects beyond its role in iron homeostasis, the endocrine effects of ERFE may not be limited to hepcidin regulation in the liver.…”

Section: Introductionmentioning

confidence: 99%

Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Coffey

Jung

Pereira

et al. 2021

Preprint

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The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia or other erythropoietic stimuli, and suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is thought to be mediated by interference with paracrine BMP signaling that regulates hepcidin transcription in hepatocytes. In anemias with ineffective erythropoiesis, ERFE is pathologically overproduced but its contribution to the clinical manifestations of these anemias is not well understood. We generated three lines of transgenic mice with graded erythroid overexpression of ERFE and showed that they developed dose-dependent iron overload, impaired hepatic BMP signaling and relative hepcidin deficiency. At the highest levels of ERFE overexpression the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive ERFE in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development.

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“…The activity of erythropoiesis is a fundamental driving force in modulating hepcidin expression, especially when iron demand increases under enhanced erythropoiesis. Under this setting, ERFE is greatly induced by EPO to suppress hepcidin through binding to BMPs 27,41 . However, whether ERFE is involved in regulating hepcidin expression during normal and abnormal pregnancy remains unkown.…”

Section: Resultsmentioning

confidence: 99%

“…ERFE, encoded by Fam132b , is a glycoprotein hormone generated by erythroblasts due to the stimulation of erythropoietin (EPO) in the bone marrow and spleen 24–26 . Recently, it was discovered that ERFE competes with BMP6 for binding to BMP receptors on the surface of hepatocytes, resulting in compromised BMP‐SMAD1/5/8 signalling in driving hepcidin expression 27 . As a consequence, iron absorption and iron recycling are enhanced to promote the availability of iron supply for the erythropoiesis 27,28 .…”

Section: Introductionmentioning

confidence: 99%

Disordered serum erythroferrone and hepcidin levels as indicators of the spontaneous abortion occurrence during early pregnancy in humans

Wei

Liu

et al. 2020

Br J Haematol

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Summary Spontaneous abortion is a common, detrimental outcome of pregnancy, and can be induced by a variety of factors, including pathophysiological conditions and socioeconomic circumstances. Despite numerous studies examining the aetiology of spontaneous abortion, there is limited understanding of the disordered iron transportation between mother and fetus through the placenta. Recently, erythroferrone (ERFE) was recognized as a novel negative regulator of hepcidin that can elevate nutritional iron absorption and macrophagic iron egress for enhanced erythropoiesis. However, its diagnostic significance in different disease conditions associated with iron remains poorly understood. In the current study, we discovered disordered maternal iron homeostasis in women who had spontaneous abortions during early pregnancy, as characterized by increased serum iron and hepcidin levels, and conversely, reduced serum ERFE levels, compared to healthy control individuals and women with normal pregnancy. Comprehensive statistical analyses revealed the correlation between different variables and pregnancy status, signifying the pronounced diagnostic value of an increased ratio of serum hepcidin and ERFE (HE ratio) in recognizing adverse pregnancy status. In contrast to previous non‐selective discrete surrogates, such as iron, hepcidin and ferritin, the HE ratio may otherwise stand for a novel and more representative hallmark for early spontaneous abortion.

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Erythroferrone Inhibits the Induction of Hepcidin By BMP6

Cited by 23 publications

References 9 publications

C-FGF23 peptide alleviates hypoferremia during acute inflammation

C-FGF23 peptide alleviates hypoferremia during acute inflammation

Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Disordered serum erythroferrone and hepcidin levels as indicators of the spontaneous abortion occurrence during early pregnancy in humans

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