Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Abstract

Key Points• Hyperactivation of the BMP-SMAD pathway blunts EPO-mediated hepcidin inhibition.• Lack of BMP-SMAD pathway inhibition by matriptase-2 abrogates the ERFEmediated hepcidin suppression in response to EPO.Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the

A Red Carpet for Iron Metabolism

“…Genetic inactivation of TMPRSS6 preserved the iron overload of Hjv − / − mice, supporting the notion that HJV is a likely substrate for TMPRSS6 (Finberg et al, 2010). Genetic experiments further indicate that TMPRSS6 requires functional BMP6/SMAD signaling for its activity (Nai et al, 2016). EPO was tested as a therapeutic for IRIDA.…”

Erythroferrone and matriptase‐2 independently regulate hepcidin expression

“…Previous studies have shown that hepcidin production was not affected by EPO in Tmprss6 mutant mice 4 . 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 production 5 . We therefore examined the crosstalk between ERFE and matriptase-2 in mice.…”

Smad7 deficiency decreases iron and haemoglobin through hepcidin up‐regulation by multilayer compensatory mechanisms

“…Similarly, deleting Tmprss6 , which encodes a serine protease that represses hepcidin expression, causes decreased liver non‐haem iron concentration and decreased mean corpuscular volume; however, Tmprss6 knockout mice developed a more severe phenotype than Smad7 Alb/Alb mice 38. In addition, a recent study suggested that Tmprss6 plays a key role in erythroferrone‐mediated hepcidin suppression 39. In contrast, hepatic expression of Tmprss6 remains unchanged in our Smad7 Alb/Alb mice (Figure S3).…”