Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous B1/B2 globin gene deletion) mice

• Published in: Haematologica (Roma) 2015-05, Vol.100 (5), p.611-622
• Main Authors: Gelderman, Monique P, Baek, Jin Hyen, Yalamanoglu, Ayla, Puglia, Michele, Vallelian, Florence, Burla, Bo, Vostal, Jaroslav, Schaer, Dominik J, Buehler, Paul W
• Format: Article
• Language: English
• Subjects: Animals; Apoproteins - administration & dosage; beta-Globins - genetics; Blood Transfusion; Cation Transport Proteins - blood; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Erythrocyte Indices - drug effects; Female; Gene Deletion; Gene Expression; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis - pathology; Hemochromatosis - therapy; Hepcidins - blood; Iron - blood; Iron - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardium - metabolism; Myocardium - pathology; Spleen - drug effects; Spleen - metabolism; Spleen - pathology; Splenomegaly - drug therapy; Transferrin - administration & dosage; Transferrin - metabolism
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2014.117325

Intermediate beta-thalassemia has a broad spectrum of sequelae and affected subjects may require occasional blood transfusions over their lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron in plasma. The iron scavenger and transport protein transferrin is a potential treatment being studied for correction of anemia. However, transferrin may also function to prevent or reduce iron loading of tissues when exposure to non-transferrin bound iron increases. Here we evaluate the effects of apotransferrin administration on tissue iron loading and early tissue pathology in non-transfused and transfused Hbb(th3/+) mice. Mice with the Hbb(th3/+) phenotype have mild to moderate anemia and consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Chronic apotransferrin administration resulted in normalization of the anemia. Furthermore, it normalized tissue iron content in the liver, kidney and heart and attenuated early tissue changes in non-transfused Hbb(th3/+) mice. Apotransferrin treatment was also found to attenuate transfusion-mediated increases in plasma non-transferrin bound iron and associated excess tissue iron loading. These therapeutic effects were associated with normalization of transferrin saturation and suppressed plasma non-transferrin bound iron. Apotransferrin treatment modulated a fundamental iron regulatory pathway, as evidenced by decreased erythroid Fam132b gene (erythroferrone) expression, increased liver hepcidin gene expression and plasma hepcidin-25 levels and consequently reduced intestinal ferroportin-1 in apotransferrin-treated thalassemic mice.