Bone Abstracts

A decrease or absence of beta-globin production in erythroid cells causes a hereditary anemic disorder known as beta-thalassemia, which is associated with ineffective erythropoiesis, iron overload, growth retardation, osteopenia, and osteoporosis. Our recent investigation revealed that beta-thalassemia led to osteoclast-mediated bone resorption and the impaired intestinal calcium absorption, the latter of which modestly responded to conventional 1,25-dihydroxyvitamin D₃ supplementation. In the present study, hemizygous beta-globin knockout thalassemic mice were used to investigate how to rescue calcium absorption. The study has been approved by institutional animal care and use committee. The results showed that transepithelial calcium flux across the duodenal epithelia of thalassemic mice was inversely correlated with the iron flux, as determined by ⁴⁵Ca and ⁵⁹Fe radioactive tracers in Ussing chamber studies. In addition to changes in iron and calcium transport, thalassemic mice also exhibited a lower paracellular flux of zinc as compared to the wild-type littermates. Iron hyperabsorption in beta-thalassemic mice probably resulted from overexpression of apical iron transporters, particularly divalent metal transporter (DMT)-1, which was apparently prevented by a liver-derived hormone hepcidin. Direct exposure to hepcidin in Ussing chamber led to downregulation of DMT1 protein expression and inhibition of transepithelial iron transport concurrently with stimulation of calcium absorption. The hepcidin-induced transcellular calcium transport was markedly diminished by inhibitors of Na⁺/Ca²⁺ exchanger 1 and plasma membrane Ca²⁺-ATPase, suggesting that hepcidin predominantly modulated the transcellular calcium transport rather paracellular transport. In conclusion, beta-thalassemia leads to calcium malabsorption and iron hyperabsorption, both of which can be rescued by hepcidin administration.