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Haematologica. 2016 Mar;101(3):297-308. doi: 10.3324/haematol.2015.127902. Epub 2015 Dec 3.

Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation.

Author information

1
Erythropoiesis Laboratory, LFKRI, New York Blood Center, NY, USA.
2
Erythropoiesis Laboratory, LFKRI, New York Blood Center, NY, USA Central South University, Changsha, PR China.
3
Flow Cytometry Core Laboratory, LFKRI, New York Blood Center, NY, USA.
4
Erythropoiesis Laboratory, LFKRI, New York Blood Center, NY, USA University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
5
Intrinsic Lifesciences, LLC, La Jolla, CA, USA.
6
Central South University, Changsha, PR China.
7
University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
8
The Feinstein Institute for Medical Research, Manhasset, NY, USA.
9
Weill Cornell Medical College, NY, USA.
10
Saint Louis University, MO, USA.
11
Erythropoiesis Laboratory, LFKRI, New York Blood Center, NY, USA yginzburg@nybloodcenter.org.

Abstract

Iron overload results in significant morbidity and mortality in β-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in β-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbb(th1/th1) (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes.

PMID:
26635037
PMCID:
PMC4815721
DOI:
10.3324/haematol.2015.127902
[Indexed for MEDLINE]
Free PMC Article

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