To understand how things work normally, scientists often explore diseases and through understanding how things go awry, piece together the normal orchestra of normal bodily functions. In that way, scientists at New York Blood Center recently gained a greater understanding of how iron regulation occurs. Iron is the body’s main building block for hemoglobin, the molecule that makes blood its red color and carries oxygen to all cells in the body. Because humans do not have a physiological mechanism for excreting iron, it is mainly controlled at the absorption end, in the intestine. In addition, most of the body’s iron comes from the breakdown of old cells, to re-use the component for making new cells. Extracting iron from food and from recycled cells is under the regulation of a recently discovered hormone, hepcidin, a hormone produced in the liver to negatively regulate iron absorption and recycling. This means that increased hepcidin will result in less circulating iron and vice versa. Diseases like β-thalassemia, a type of genetically inherited anemia, are associated with expanded blood making machinery, in response to anemia, and iron overload, as a consequence of insufficient hepcidin, both contributing to the multiple causes of morbidity and mortality in these patients. Even more recently, after decades of postulating that the body must have a regulator of hepcidin that originates in its blood making organs, scientists discovered a new hormone, erythroferrone, produced in the bone marrow that negatively regulates hepcidin in conditions of anemia.

Fig. 1. Proposed working model of hepcidin regulation in transferrin treated β-thalassemic mice. Apo-transferrin treatment induces circulating BMP2, decreases circulating erythroferrone, and decreases activation of MEK/ERK1/2 in hepatocytes, resulting in increased nuclear signaling and hepcidin expression.

The details regarding how erythroferrone regulates hepcidin are still unclear but hepcidin regulation in general involves multiple receptor binding pathways and cell signaling pathways. Typically, iron is bound in circulation to transferrin; this iron-transferrin complex binds transferrin receptors on cell membranes to gain entry into cells. To regulate hepcidin, iron-transferrin complex binds transferrin receptors on hepatocytes but instead of entering into the cell, a signal is sent to the nucleus that triggers the production of hepcidin. In addition to iron-transferrin complex binding transferrin receptor, additional regulators, known collectively as bone morphogenic proteins (BMPs), bind BMP receptors on hepatocytes and send a message via several pathways to regulate hepcidin production in the nucleus. The classic signaling pathway that communicates systemic iron needs via BMPs is decapentaplegic (Smad) 1/5/8 signaling pathway. An alternative MEK/ERK1/2 pathway has also been proposed in hepcidin regulation, possibly through the Smad pathway, but its precise function has not been fully elucidated.

We previously demonstrated that treating a mouse model of β-thalassemia with exogenous transferrin results in reversal of anemia and increased hepcidin. To understand the mechanisms of hepcidin regulation in transferrin-treated β-thalassemic mice, we explore iron-related parameters in circulation and in hepatocytes. Our findings demonstrate that transferrin results in increased circulating BMP2 and decreased erythroferrone expression in the bone marrow in treated β-thalassemic mice, both correlating with increased hepcidin despite reversal of iron overload in transferrin-treated β-thalassemic mice. Additionally, our findings reveal that MEK/ERK1/2 signaling is decreased in hepatocytes from transferrin-treated β-thalassemic mice and correlates with increased evidence of nuclear stimulation of hepcidin. We hypothesize that BMP2 is a previously unexplored suppressor of MEK/ERK1/2 pathway to induce hepcidin and prevent iron overload (Fig. 1). The mechanism by which this occurs is not yet clear. Taken together, our data present mechanisms for hepcidin de-repression in transferrin-treated β-thalassemic mice, provide additional therapeutic targets in this pathway, and support our hypothesis that reversal of anemia and iron overload requires parallel management in β-thalassemia.

Yelena Ginzburg
Erythropoiesis Laboratory, LFKRI, New York Blood Center, NY, USA

Publication

Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation.
Chen H, Choesang T, Li H, Sun S, Pham P, Bao W, Feola M, Westerman M, Li G, Follenzi A, Blanc L, Rivella S, Fleming RE, Ginzburg YZ
Haematologica. 2016 Mar

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