The production of the iron-regulatory hormone hepcidin is physiologically suppressed during increased erythropoietic activity. Hepcidin suppression increases iron availability to meet the additional iron demand of expanded hemoglobin synthesis. Under the influence of erythropoietin (EPO), the hormone erythroferrone (ERFE) is secreted by erythroid precursors in the bone marrow and spleen, and suppresses hepcidin synthesis to facilitate the recovery from anemia1, 2. However, the mechanism by which ERFE suppresses hepcidin is unknown.

In contrast with forms of anemia in which hepcidin is suppressed, patients with ironrefractory iron deficiency anemia (IRIDA) 3, a disease caused by mutations in transmembrane serine protease 6 (TMPRSS6) which result in pathological activation of the BMP/Smad signaling, exhibit increased hepcidin production despite a severe anemia and elevated EPO levels. Previous studies have shown that hepcidin production was not affected by EPO in Tmprss6 mutant mice4. More recently, Nai and colleagues suggested that matriptase-2 may act downstream of EPO to dampen the signaling through the BMP-Smad regulatory pathway and allow ERFE to repress hepcidin production5. We therefore examined the crosstalk between ERFE and matriptase-2 in mice.