By Sabina I. Swierczek, PhD, and Josef T. Prchal, MD
2008-03-01
Drs. Swierczek and Prchal indicated no relevant conflicts of interest.
Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096-101.
Our understanding of the regulation of iron homeostasis has been
greatly facilitated by the discovery of the iron-regulatory protein
hepcidin. This small peptide regulates cellular iron export by binding
and triggering internalization and degradation of the iron export
protein ferroportin. This alters the availability of iron by shifting
the serum iron away from erythropoiesis to macrophages and by
inhibiting iron absorption by the duodenum.1 As such, an
understanding of the regulation of hepcidin has been central to the
pathophysiology of anemia of chronic disease (inflammation induces
hepcidin expression by the IL-6 pathway) and various types of
hemochromatosis (wherein hepcidin is low).2 However, while
understanding hepcidin regulation largely clarified its interaction
with iron control mechanisms that were coined by a seminal paper of
Clem Finch as a "stores regulator," "hypoxia regulator," and
"inflammatory regulator," it failed, however, to explain the increased
iron absorption seen in thalassemias and sideroblastic anemias. This
mysterious crosstalk between hyperactive inefficient erythropoiesis and
anemia was termed the "erythroid regulator."3 Interestingly,
in some anemic states with hyperactive erythropoiesis, such as in
sickle cell disease, hepcidin is not decreased, and clinically
significant iron overload is uncommon, while in thalassemia major and
intermedia hepcidin is markedly decreased with a tendency to iron
overload that is unrelated to red cell transfusions.4
The study from Jeff Miller’s laboratory is an important step in
solving the identity of the erythroid regulator. In their paper, Tanno
and colleagues propose that iron overload in ß-thalassemia patients may
result from inhibition of hepcidin by high levels of growth
differentiations of factor 15 (GDF15), a member of the transforming
growth factor-ß (TGFB) superfamily. They followed up on a
well-established fact that in patients with ß-thalassemia, hepcidin
expression is decreased, speculating that the thalassemic erythroid
precursors produce a hepcidin repressor during their hyperactive and
largely apoptotic maturation. Based on this hypothesis, the authors
examined transcriptional profiles of TGFB members in primary
erythroblasts and detected increased expression and secretion of GDF15
during erythroblast maturation in normal controls. The investigators
then hypothesized that elevated numbers of apoptotic erythroblasts in
patients with thalassemia might produce increased levels of GDF15.
Indeed, they report that in some ß-thalassemia patients, serum levels
of GDF15 are dramatically increased and that the serum concentration of
GDF15 correlated with elevated erythroblast numbers and iron overload
in ß-thalassemia. To examine the regulation of hepcidin expression by
GDF15, the authors measured hepcidin expression in primary hepatocytes
(cells producing hepcidin) that were exposed to the sera with normal
and elevated levels of GDF15, and found that hepcidin production was
suppressed by high levels of GDF15. Very high levels of GDF15, however,
could not completely suppress hepcidin expression. They also noted that
depletion of GDF15 significantly increased hepcidin expression in
ß-thalassemia serum. These observations suggest that
erythroblast-produced GDF15 is involved in the suppression of hepcidin
production and thus leads to augmented iron absorption in
ß-thalassemia. However, these studies also suggest that GDF15 is not
the sole regulator of hepcidin expression by hyperactive erythropoiesis.
Other disorders involved with ineffective
erythropoiesis or unexplained iron-loading pathology are being tested
for GDF15 overexpression. Tanno and colleagues have also evaluated a
small number of MDS patients and have shown a much lower level of GDF15
compared with levels seen in ß-thalassemia. These data, and data that
conflicted with the central role of GDF15, presented by Photis Beris at
this year’s ASH annual meeting based on studies of other anemic
disorders associated with iron overload and ineffective erythropoiesis,
suggest that the identity of the erythroid regulator of hepcidin
expression is still not fully resolved. However, in our judgment, this
paper is an important step toward the eventual elucidation of the still
mysterious erythroid regulator of iron absorption.
- Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood. 2005;105:4103-5.
- Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117:285-97.
- Finch C. Regulators of iron balance in humans. Blood. 1994;84:1697-702.
- Nemeth E, Ganz T. Hepcidin and iron-loading anemias. Haematologica. 2006;91:727-32.
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