We have recently shown that hepcidin expression undergoes a significant down regulation in the liver of a thalassaemia intermedia mouse model (TIM) C57Bl/6 Hbbth3/+. (

Adamsky K. et al.
BJH
2004
;
124
(1):
123
–4
). We extended these studies to a b-thalassemia major mouse model (TMM) generated via engraftment with beta-globin-null (Hbbth3/th3) fetal liver cells. The resulting phenotype displayed considerably more severe symptoms than the TIM: the TMM succumbed to ineffective erythropoiesis within 60 days, developed massive splenomegaly, severe anemia, extramedullary hematopoiesis and hepatic iron overload. The expression levels of various iron metabolism-related genes (normalized to b-actin) were analyzed by quantitative RT-PCR on RNA extracted from the livers of adult mice. When compared to wild-type (WT) C57Bl/6 mice, the liver mRNA expression levels of TMM were markedly reduced for hepcidin and TfR2 (16 and 3 fold respectively), markedly increased for the lipocalin NGAL and transferrin receptor 1 (TfR1) (2.7 and 3.6 fold respectively), moderately increased for the ferroportin transporter (IREG1) (1.4 fold) and unaltered for the hemochromatosis gene (HFE). A possible mechanism that could explain the decreased expression of liver hepcidin in thalassaemia is one based on a putative regulatory serum factor that is associated with enhanced erythropoietic activity. In order to assess this hypothesis we compared the hepcidin inductive capacity of sera from iron-overloaded patients that either had or had not enhanced erythropoiesis, namely thalassemia and hemochromatosis, respectively. These included the following individuals: 14 with β-thalassemia major, 22 with hereditary hemochromatosis (HFE 282C mutation) and 3 healthy. The human sera were analyzed in terms of their capacity to modulate expression of iron-related genes in human hepatoma HepG2 cells, using quantitative RT-PCR. Hepcidin expression evoked by thalassemic sera was an average of 3 fold lower than that evoked by normal human serum, whereas hemochromatotic sera evoked an average of 7.83 fold increase. The down regulating effect of thalassemic sera on hepcidin expression, suggests the possible involvement of an upstream factor whose serum levels might increase in thalassemia due to ineffective erythropoiesis, i.e. an “erythropoietic regulator”. The effect of such an “erythropoietic regulator” is assumed to override the expected increase in hepcidin expression that results from the “stores regulator” which is responsive to iron overload such as in hemochromatosis (where there is no ineffective erythropoiesis). The reduced hepcidin expression found in thalassaemia might explain the increased enteric iron absorption whose extent could be moderated either by factors that increase hepcidin expression or by administration of hepcidin itself.

Topics:
hemochromatosis, hepatocytes, hepcidin, iron, serum, thalassemia, ineffective erythropoiesis, iron overload, quantitative real-time polymerase chain reaction, transferrin receptors

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2005, The American Society of Hematology
2004
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