Abstract
BackgroundIron overload is one of common complications of β-thalassemia. Systemic iron homeostasis is regulated by iron-regulatory hormone, hepcidin, which inhibits intestinal iron absorption and iron recycling by reticuloendothelial system. In addition, body iron status and requirement can be altered with age. In adolescence, iron requirement is increased due to blood volume expansion and growth spurt. Heterozygous β-globin knockout mice (Hbbth3/+; BKO) is a mouse model of thalassemia widely used to study iron homeostasis under this pathological condition. However, effects of age on iron homeostasis, particularly the expression of genes involved in hemoglobin metabolism as well as erythroid regulators in the spleen, during adolescence have not been explored in this mouse model.MethodsIron parameters as well as the mRNA expression of hepcidin and genes involved in iron transport and metabolism in wildtype (WT) and BKO mice during adolescence (6–7 weeks old) and adulthood (16–20 weeks old) were analyzed and compared by 2-way ANOVA.ResultsThe transition of adolescence to adulthood was associated with reductions in duodenal iron transporter mRNA expression and serum iron levels of both WT and BKO mice. Erythrocyte parameters in BKO mice remained abnormal in both age groups despite persistent induction of genes involved in hemoglobin metabolism in the spleen and progressively increased extramedullary erythropiesis. In BKO mice, adulthood was associated with increased liver hepcidin and ferroportin mRNA expression along with splenic erythroferrone mRNA suppression compared to adolescence.ConclusionOur results demonstrate that iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood. The present study underscores the importance of the age of thalassemic mice in the study of molecular or pathophysiological changes under thalassemic condition.
Highlights
Iron, one of essential trace elements, is involved in several biological processes such as oxidative phosphorylation and hemoglobin synthesis (Jandl et al, 1959; Pollycove & Mortimer, 1961; Hentze, Muckenthaler & Andrews, 2004)
The acquired iron is used for the production of hemoglobin which involves several proteins including mitoferrin 1 (Mfrn1) a mitochondrial iron transporter and 5-aminolevulinic acid synthase 2 (ALAS2) an enzyme catalyzing the first reaction of erythroid heme biosynthetic pathway (Shaw et al, 2006; Paradkar et al, 2009; Amigo et al, 2011; Lane et al, 2015)
But not hematological parameters, of thalassemic mice were affected by age To explore whether hematological parameters were affected by the age of mice, EDTA blood samples from WT and BKO mice aged 6–7 weeks and 16–20 weeks were analyzed for complete blood count
Summary
One of essential trace elements, is involved in several biological processes such as oxidative phosphorylation and hemoglobin synthesis (Jandl et al, 1959; Pollycove & Mortimer, 1961; Hentze, Muckenthaler & Andrews, 2004). Upon erythrophagocytosis of senescent erythrocytes by RE cells, hemoglobin is degraded by heme oxygenase-1 (HO-1) and iron is released into the circulation for reutilization. This RE iron recycling process accounts for the majority of iron in the plasma. Effects of age on iron homeostasis, the expression of genes involved in hemoglobin metabolism as well as erythroid regulators in the spleen, during adolescence have not been explored in this mouse model. Methods: Iron parameters as well as the mRNA expression of hepcidin and genes involved in iron transport and metabolism in wildtype (WT) and BKO mice during adolescence (6–7 weeks old) and adulthood (16–20 weeks old) were analyzed and compared by 2-way ANOVA. The present study underscores the importance of the age of thalassemic mice in the study of molecular or pathophysiological changes under thalassemic condition
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