GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

Abstract

Hepcidin (HAMP) synthesis is suppressed by erythropoiesis to increase iron availability for red blood cell production. This effect is thought to result from factors secreted by erythroid precursors. Growth differentiation factor 11 (GDF11) expression was recently shown to increase in erythroid cells of b-thalassaemia, and decrease with improvement in anaemia. Whether GDF11 regulates hepatic HAMP production has never been experimentally studied. Here, we explore GDF11 function during erythropoiesistriggered HAMP suppression. Our results confirm that exogenous erythropoietin significantly increases Gdf11 as well as Erfe (erythroferrone) expression, and Gdf11 is also increased, albeit at a lower degree than Erfe, in phlebotomized wild type and b-thalassaemic mice. GDF11 is expressed predominantly in erythroid burst forming unit-and erythroid colony-forming unit-cells during erythropoiesis. Exogeneous GDF11 administration results in HAMP suppression in vivo and in vitro. Furthermore, exogenous GDF11 decreases BMP-SMAD signalling, enhances SMAD ubiquitin regulatory factor 1 (SMURF1) expression and induces ERK1/2 (MAPK3/1) signalling. ERK1/2 signalling activation is required for GDF11 or SMURF1mediated suppression in BMP-SMAD signalling and HAMP expression. This research newly characterizes GDF11 in erythropoiesis-mediated HAMP suppression, in addition to ERFE.

The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

“…The new therapeutic luspatercept, which acts as a trap ligand to inactivate GDF11, has been shown to increase RBC count and hematocrit in healthy and anemic individuals [ 132 , 133 ]. While it has been demonstrated that GDF11 can inhibit hepcidin levels, thereby connecting erythropoiesis to iron metabolism, other studies have questioned the role of GDF11, since the murine homolog of luspatercept, RAP-536, also enhanced erythropoiesis in GDF11 KO mice [ 134 , 135 ]. Therefore, further studies are needed to investigate the role of GDF11 in human erythropoiesis and iron regulation.…”

The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia

“…Hepcidin binds to ferroportin on enterocytes and iron-storing cells like macrophages, resulting in an internalization and degradation of the hepcidin-ferroportin complex and thus effectively shuts down nutritional iron absorption and iron release from internal iron storage. Hepcidin expression is controlled by regulatory feedback mechanisms that involve active erythropoiesis: erythroblast-derived erythroferrone (ERFE), growth differentiation factor 11 (GDF11), growth differentiation factor 15 (GDF15) and twisted gastrulation protein homolog 1 (TWSG1) have been shown to influence hepatic hepcidin secretion, thus linking erythropoietic iron demand to iron supply (15)(16)(17)(18).…”

Growth differentiation factor 11: a “rejuvenation factor” involved in regulation of age-related diseases?

“…MitoTEMPO, a mitochondrion-targeted ROS inhibitor, inhibits the GDF11-induced activation of c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase; thus, the GDF11-induced activation of c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase can be modified by ROS status [ 37 ]. Recently, ERK1/2 signaling was found to be activated by GDF11, which downregulated bone morphogenetic protein–SMAD signaling and hepcidin activity [ 38 ].…”