Anemia of Chronic Disease (ACD) or Anemia of Inflammation (AI) is prevalent in patients with chronic infection, autoimmune disease, cancer and chronic kidney disease. ACD is associated with poor prognosis and lower quality of life. Management of ACD using intravenous iron and erythropoiesis stimulating agents (ESAs) are ineffective for some patients and are not without adverse effects, driving the need for new alternative therapies. Recent advances in our understanding of the molecular mechanisms of iron regulation reveal that increased hepcidin, the iron regulatory hormone, is a key factor in the development of ACD. In this review, we will summarize the role of hepcidin in iron homeostasis, its contribution to the pathophysiology of ACD, and novel strategies that modulate hepcidin and its target ferroportin for the treatment of ACD.

Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TM-PRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TM-PRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels. (Blood. 2011;118(3): 747-756) IntroductionTransmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2 (MTP-2), a transmembrane serine protease produced by the liver, 1,2 was recently identified as a critical gene for iron homeostasis. 3,4 In both humans and mice, mutations in the TMPRSS6 gene lead to a strong increase in hepcidin expression, resulting in a dramatic decrease in ferroportin expression, and severe iron deficiency anemia that is unresponsive to oral iron treatment but partially responsive to parenteral iron therapy (IRIDA). [3][4][5][6] Moreover, genome-wide association studies identified common TMPRSS6 variants associated with hematologic parameters 7-9 and serum iron concentration, 8,10 highlighting that TMPRSS6 is important in the control of iron homeostasis and normal erythropoiesis. It was recently proposed that the mechanism by which TMPRSS6 inhibits hepcidin expression is by down-regulation of the bone morphogenetic protein (BMP)-SMAD signaling pathway via proteolytic cleavage of the BMP coreceptor hemojuvelin. 11,12 Hepcidin is an iron-regulated hepatic peptide hormone that controls iron absorption at the intestinal level and iron release from macrophages and hepatocytes. Hepcidin binds to the plasma membrane iron exporter ferroportin and induces its endocytosis and proteolysis, preventing release of iron into plasma. 13 Iron 14 and inflammatory cytokines (eg, interleukin-6) 15 stimulate hepcidin expression, leading to reduced plasma iron levels. In contrast, hypoxia, high erythropoietic activity, and iron deficiency inhibit hepcidin expression. 16 The role of the BMP-SMAD signaling pathway in regulating hepcidin...