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Blood Spotlight
Molecular liaisons between erythropoiesis and iron metabolism
Leon Kautz and Elizabeta Nemeth
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
Although most circulating iron in blood
plasma is destined for erythropoiesis, the
mechanisms by which erythropoietic demand modulates the iron supply (“erythroid
regulators”) remain largely unknown. Iron
absorption, plasma iron concentrations, and
tissue iron distribution are tightly controlled
by the liver-produced hormone hepcidin.
During the last decade, much progress has
been made in elucidating hepcidin regulation
by iron and inflammation. This review discusses the less understood mechanisms
and mediators of hepcidin suppression in
physiologicallyandpathologicallystimulated
erythropoiesis. (Blood. 2014;124(4):479-482)
Introduction
Iron is an essential functional component of erythrocyte
hemoglobin, therefore the production of erythrocytes requires the
timely delivery of iron to erythroid precursors. The process of
erythropoiesis is by far the largest consumer of iron in the body, with
red cells containing two-thirds of the total body iron. Five liters of
human adult blood contains ;2.5 3 1013 erythrocytes that have an
average lifespan of 120 days. Steady-state erythropoiesis involves the
production of 200 billion new red blood cells per day or 2.4 million per
second.1 This requires a daily supply of 20 to 25 mg of iron, in the form
of holotransferrin. The transferrin compartment contains only about
3 mg of iron at any time, and turns over every few hours. Most of the iron
for erythropoiesis in humans is supplied by the recycling of senescent
red blood cells by macrophages, a process known as erythrophagocytosis which provides ;20 to 25 mg of iron per day. In the steady
state, intestinal absorption of dietary iron amounts to only 1 to 2 mg per
day (,0.05% of total body iron), sufficient to compensate for the small
amount of iron lost from the body through desquamation of epithelial
cells in the intestine and the skin or minor blood loss.
Iron supply to the marrow comes under particular strain after
hemorrhage, hemolysis, and other conditions that trigger stress
erythropoiesis. When erythrocytes are lost, critical signals facilitating
the provision of iron for restorative erythropoiesis are expected to occur
within hours, as rapid recovery of red cell mass and oxygen carrying
capacity confers obvious evolutionary advantages. During maximally
stimulated erythropoiesis, hemoglobin synthesis and therefore iron
consumption by the bone marrow can increase up to 10-fold2 and must
be matched by a comparable increase in dietary iron absorption and in
the release of iron from stores. Failure to match iron supply to demand
would rapidly deplete the small iron-transferrin compartment and limit
the iron supply not only for hemoglobin synthesis but also for all
other iron-dependent processes. However, the mechanism by which
erythropoiesis modulates iron homeostasis, historically referred to as
the “erythroid regulator,”2 is poorly understood.
Hepcidin: the link between erythropoiesis and
iron regulation
The liver-produced hormone hepcidin has emerged as the main
circulating regulator of iron absorption and tissue distribution,3 and
Submitted May 2, 2014; accepted May 27, 2014. Prepublished online as Blood
First Edition paper, May 29, 2014; DOI 10.1182/blood-2014-05-516252.
BLOOD, 24 JULY 2014 x VOLUME 124, NUMBER 4
represents the distal component of the “erythroid regulator”
mechanism. Hepcidin acts by binding to ferroportin, the sole known
cellular iron exporter, leading to ubiquitination, internalization, and
degradation of ferroportin in lysosomes.4 Under the influence of high
hepcidin concentrations, ferroportin is depleted from cell membranes, iron is retained in iron-exporting cells, and the flow of iron
into plasma is decreased. Conversely, when hepcidin production
is reduced, stabilization of ferroportin at the cellular membrane
promotes the absorption of dietary iron in the duodenum, increases
the release of iron from macrophages that recycle old erythrocytes
and other cells, and allows the mobilization of stored iron from
hepatocytes (Figure 1). Reflecting the greatly increased demand for
iron, hepcidin is suppressed in conditions associated with accelerated
erythropoiesis, including anemias caused by bleeding, hemolysis,
or iron deficiency, and in hereditary anemias with ineffective
erythropoiesis.3 The mechanism(s) involved in these responses are
only beginning to be understood.
Disordered interaction between iron
metabolism and erythropoiesis
Disruption of homeostatic mechanisms regulating hepcidin can lead
to impaired erythropoiesis. Increased circulating hepcidin causes or
contributes to iron-restrictive anemia in inflammatory disorders,
chronic kidney diseases, cancer, and iron-refractory iron deficiency
anemia (IRIDA).3 Multiple pathogenic mechanisms can increase
hepcidin concentrations in blood plasma. In inflammatory disorders,
hepcidin synthesis is stimulated by proinflammatory cytokines, most
prominently interleukin-6. In chronic kidney disease, not only
inflammation but also decreased renal clearance of hepcidin peptide
seem to contribute to higher hepcidin levels. In the genetic disease
IRIDA, hepcidin is increased due to loss-of-function mutations in
matriptase-2 (aka TMPRSS6), a negative regulator of hepcidin
transcription. In all these conditions, the increase in plasma hepcidin
concentrations is the cause of hypoferremia and inadequate iron
supply for erythropoiesis.
Conversely, pathological erythropoiesis can cause iron disorders.
Ineffective erythropoiesis suppresses hepcidin production,5,6 which
causes hyperabsorption of dietary iron and iron overload even
© 2014 by The American Society of Hematology
479
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480
KAUTZ and NEMETH
BLOOD, 24 JULY 2014 x VOLUME 124, NUMBER 4
decrease precedes any changes in transferrin saturation or other
known iron-related parameters.13 Rather, accumulating evidence
suggests that the erythroid regulator of hepcidin is a circulating factor
produced by erythroid precursors in the bone marrow in response to
EPO (Figures 1-2).
Candidate erythroid factors regulating
hepcidin
Figure 1. Hepcidin coordinates iron supply for erythropoiesis. Hepcidin controls
major iron flows into plasma by causing degradation of its receptor ferroportin. After
erythropoietic stimulation, erythroid precursors secrete 1 or more mediators
(erythroid factors) that suppress hepcidin production in the liver, resulting in
increased iron supply to the bone marrow. ERFE has been proposed to mediate
hepcidin suppression in both physiological (eg, after hemorrhage) and pathological
conditions (eg, ineffective erythropoiesis), whereas GDF15 and TWSG1 may only
play a role in iron-loading anemias. Other erythroid regulators may exist but have yet
to be identified.
in the absence of erythrocyte transfusions.5 Genetic disorders
with ineffective erythropoiesis include thalassemias and congenital
dyserythropoietic anemias. In these conditions, erythrocyte precursors massively expand but do not mature into erythrocytes and mostly
undergo apoptosis at the erythroblast stage.7 Transfusions partially
relieve the erythropoietin (EPO)-driven expansion of ineffective
erythropoiesis and raise hepcidin concentrations,6 but still cause
iron overload owing to the iron content of transfused blood. In
thalassemia, iron overload may further aggravate ineffective erythropoiesis by stimulating erythroblast reactive oxygen species production and increasing the imbalance between globin chains.8
Whether the same or overlapping hepcidin suppressor(s) function
both in ineffective erythropoiesis and in physiological recovery from
hemorrhage is unknown but considered likely as the 2 situations
share the common feature of high levels of EPO and expansion
of erythroblast populations.
Two members of the transforming growth factor-b superfamily,
growth differentiation factor 15 (GDF15) and twisted gastrulation
(TWSG1), have been proposed as pathological suppressors of
hepcidin in ineffective erythropoiesis.14,15 Although synthesized
in many other tissues, these factors are also expressed during late
(GDF15) and early (TWSG1) stages of human erythroblast differentiation ex vivo.14 GDF15 is known to play roles in inflammation,
cancer, cardiovascular diseases, and obesity through incompletely
understood mechanisms,16 whereas TWSG1 modulates bone morphogenetic protein activity during embryonic development and in
multiple adult tissues.17
In vitro, high concentrations of GDF15 or TWSG1 suppressed
hepcidin expression in primary hepatocytes or hepatocyte cell
lines.14,15 However, the role of GDF15 and TWSG1 in hepcidin
suppression in vivo is less clear. Twsg1 messenger RNA (mRNA)
expression is increased in the spleen, liver, and, to a much lesser
extent, the bone marrow of the murine b-thalassemia models,12,15,18
but the contribution of increased TWSG1 to pathological hepcidin
suppression is unknown. It is also not known whether TWSG1 is
increased in human patients with ineffective erythropoiesis. TWSG1
does not appear to be involved in physiological hepcidin suppression
by increased erythropoiesis in mice: Twsg1 mRNA was unchanged
in the bone marrow and spleen of Vhl2/2 mice that have high Epo
levels,12 or in wild-type (WT) mice after Epo administration,12 or in
WT mice after severe blood loss.19
GDF15 was proposed to suppress hepcidin in b-thalassemia or
congenital dyserythropoietic anemia in humans as its blood levels are
high in ineffective erythropoiesis.14,20 However, direct evidence for
Hepcidin regulation by erythropoiesis
Increased EPO is the primary stimulus for erythropoietic activity,
and both EPO concentrations and indicators of erythropoietic
activity are inversely correlated with hepcidin expression in patients
with b-thalassemia.5,6 However, EPO does not seem to have a direct
effect on hepatic hepcidin production: EPO injections in mice with
ablated bone marrow failed to suppress hepcidin.9,10 The transcription factor hypoxia-inducible factor (HIF), a key mediator of cellular
adaptation to hypoxia, directly regulates renal and hepatic EPO
synthesis during anemia, and was also considered a candidate
regulator of hepcidin transcription. Nevertheless, recent evidence
indicates that hepcidin suppression by the HIF pathway is indirect,
through the EPO-mediated stimulation of erythropoiesis.11,12
Increased iron utilization after EPO administration is also not the
mediator of hepcidin suppression because the dramatic hepcidin
Figure 2. Proposed mechanism of action of the erythroid regulator ERFE. After
blood loss, decreased oxygen delivery is sensed in the kidneys, stabilizing HIF and
inducing EPO production. Binding of EPO to its receptors on erythroid progenitors
in the bone marrow and the spleen leads to the rapid production of ERFE via the
JAK2/STAT5 signaling pathway. ERFE is then secreted into the circulation and acts
directly on hepatocytes to signal for hepcidin suppression in order to increase the
iron flow into plasma for new red blood cell synthesis.
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BLOOD, 24 JULY 2014 x VOLUME 124, NUMBER 4
the role of GDF15 is still lacking. One of the difficulties is the
species-specific difference in the tissue expression and regulation of
Gdf15. Unlike their human counterparts, mouse erythoblasts do not
produce Gdf15 during differentiation in vitro.21 Furthermore, Gdf15
is not increased in murine b-thalassemia,12,18,19 in contrast to human
disease. This suggests that mouse models may not be appropriate to
study the role of Gdf15 in hepcidin regulation. However, some
parallels have been reported between human and mouse Gdf15
regulation. Elevated EPO was associated with higher Gdf15
expression in certain mouse models: Vhl2/2 mice with high EPO
levels or WT mice injected with EPO both increased Gdf15
expression in bone marrow and spleen, although this translated into
only a small increase in serum concentrations.12 Similarly, small
increases in serum GDF15 were observed following ascent to high
altitude22 but these levels were much lower than the concentrations
observed in thalassemia patients. Single injection of EPO in human
volunteers resulted in either no induction of GDF1513 or a small
induction when a large EPO dose was used.23 In both studies,
hepcidin levels were dramatically decreased. Thus, GDF15 does not
appear to be necessary for acute hepcidin regulation by EPO.
Only one study directly assessed the role of Gdf15 in hepcidin
regulation by using Gdf15 knockout mice.19 Hepcidin response to
phlebotomy was assessed on day 3, after removing a total of 0.8 mL
of blood over the first 2 days. WT mice increased Gdf15 mRNA
in the bone marrow approximately threefold, but hepcidin was
similarly suppressed between Gdf15-deficient and WT mice. This
suggests that GDF15 is not necessary for physiological suppression
of hepcidin after hemorrhage in mice, although a more detailed
time-course analysis would be necessary to eliminate the role of
Gdf15 in acute hepcidin suppression (within hours after hemorrhage). In humans, subjects with iron deficiency24 or iron-deficiency
anemia25,26 had normal or only marginally elevated GDF15,27
further suggesting that GDF15 is not a physiological regulator of
hepcidin. Similarly, GDF15 did not appear to be a regulator of
hepcidin in myelodysplastic syndrome28 or chronic myeloproliferative disease.29 Thus, direct involvement of GDF15 or TWSG1 in
hepcidin regulation in humans still remains to be demonstrated.
Erythroferrone, a new regulator of hepcidin
We recently described the identification of the hormone erythroferrone (ERFE), a new erythroid regulator of hepcidin that belongs
to the C1q–tumor necrosis factor–related family of proteins.30 In
response to EPO, ERFE is rapidly produced by erythroid precursors
in the bone marrow and the spleen via signal transducer and
activator of transcription 5 (Stat5)30 (Figure 2). The canonical
Janus kinase 2 (Jak2)/Stat5 signaling pathway is a known mediator
of EPO response and stress erythropoiesis.31 Phlebotomy or EPO
administration in ERFE-knockout mice failed to suppress hepcidin,
demonstrating that ERFE is absolutely necessary for acute hepcidin
response to increased erythroid activity.30 However, our study design
focused only on early responses (first 24 hours) and we therefore
cannot exclude that other erythroid regulators may exist and intervene
later on. Lentiviral overexpression of ERFE in mice confirmed its suppressive effect on hepcidin. Treatment of primary mouse hepatocytes
with recombinant ERFE indicated that ERFE acts directly on the liver
to decrease hepcidin transcription, although the pathways involved,
including the ERFE receptor, are still unknown. Interestingly, ERFE’s
role is restricted to stress erythropoiesis and does not seem to affect
steady-state erythropoiesis as adult Erfe-deficient mice had normal
HEPCIDIN, IRON, AND ERYTHROPOIESIS
481
hematologic and iron parameters. However, even the mild stress
of expanding erythropoiesis in rapidly growing juvenile mice was
sufficient to cause transient anemia in ERFE-deficient mice.
ERFE mRNA levels were also remarkably elevated in the bone
marrow and the spleen of a mouse model of b-thalassemia intermedia
(Hbbth3/th3)30 suggesting that Erfe could be a pathological suppressor
of hepcidin in ineffective erythropoiesis. Importantly, ablation of
ERFE in thalassemic mice restored hepcidin levels to normal, and
significantly reduced the liver iron content and serum iron concentration compared with the thalassemic mice. The function of
ERFE in humans remains to be investigated, although ex vivo studies
confirm that EPO induces ERFE in human erythroid precursors.30
Further work is necessary to confirm whether ERFE is the longsought erythroid regulator responsible for hepcidin suppression and
iron overload in patients with hereditary iron-loading anemias.
Novel approaches to treat disorders
of erythropoiesis
Considering the role of increased hepcidin in iron-restricted anemias,
it is not surprising that hepcidin has become a promising target for
novel therapeutic approaches.32 Multiple agents directed at lowering
hepcidin production or interfering with hepcidin peptide activity are
under development, and several clinical trials are already under way.
Potentiating or mimicking the suppressive effect of natural erythroid
regulators of hepcidin could provide additional therapeutic options
for overcoming iron restriction in inflammatory disorders, chronic
kidney disease, or cancer.
At the other end of the spectrum, causing mild iron restriction by
increasing hepcidin in iron-loading anemias may produce surprising
therapeutic benefits. In mouse models of b-thalassemia, moderate
increase in hepcidin, caused either by transgenic hepcidin overexpression, knockdown of the negative hepcidin regulator matriptase
2, or administration of hepcidin agonists, resulted not only in less
iron loading but also improvement in anemia.8,32 The hematologic
benefits of mild iron restriction seem to be the result of decreased
a-globin precipitation, lower reactive oxygen species levels, and
decreased apoptosis.8 Similar results may be expected from
interfering with overactive erythroid regulators that suppress
hepcidin in ineffective erythropoiesis (eg, ERFE).
The interface between erythropoiesis and iron metabolism
continues to yield exciting and therapeutically promising discoveries.
Just recently, a therapy based on activin receptor ligand traps was
shown to improve anemia and diminish iron overload in mouse
models of b-thalassemia and myelodysplastic syndrome by inhibiting
GDF11, a novel regulator of erythropoiesis.33,34 It is not yet known
whether Gdf11 directly regulates iron homeostasis.
Important scientific advances made in recent years have brought
increased understanding of the intimate relationship between
erythropoiesis and iron homeostasis that will eventually benefit
patients suffering from iron disorders and anemias.
Acknowledgments
This work was supported by National Institutes of Health, National
Institute of Diabetes and Digestive and Kidney Diseases grant R01
DK90554 (E.N.) and the American Society of Hematology
(ASH) scholar award (L.K.).
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482
BLOOD, 24 JULY 2014 x VOLUME 124, NUMBER 4
KAUTZ and NEMETH
Authorship
Contribution: L.K. and E.N. wrote the paper.
Conflict-of-interest disclosure: E.N. is a cofounder, shareholder,
and officer of Intrinsic LifeSciences, a company developing hepcidin
diagnostics, and shareholder in Merganser Biotech, engaged in the
development of hepcidin-based therapeutics. The remaining author
declares no competing financial interests.
Correspondence: Elizabeta Nemeth, Department of Medicine,
UCLA, 10833 LeConte Ave, CHS 37-131, Los Angeles, CA 90095;
e-mail: [email protected].
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From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
2014 124: 479-482
doi:10.1182/blood-2014-05-516252 originally published
online May 29, 2014
Molecular liaisons between erythropoiesis and iron metabolism
Leon Kautz and Elizabeta Nemeth
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