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

Br J Haematol. 2020 Jan;188(2):321-331. doi: 10.1111/bjh.16156. Epub 2019 Aug 16.


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 β-thalassaemia, and decrease with improvement in anaemia. Whether GDF11 regulates hepatic HAMP production has never been experimentally studied. Here, we explore GDF11 function during erythropoiesis-triggered 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 β-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 SMURF1-mediated suppression in BMP-SMAD signalling and HAMP expression. This research newly characterizes GDF11 in erythropoiesis-mediated HAMP suppression, in addition to ERFE.

Keywords: GDF11; erythroid factor; erythropoiesis; hepcidin/HAMP; iron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / biosynthesis
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / pharmacology
  • Erythropoiesis / physiology
  • Erythropoietin / pharmacology
  • Growth Differentiation Factors / biosynthesis
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism*
  • Growth Differentiation Factors / pharmacology
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Hepcidins / antagonists & inhibitors*
  • Hepcidins / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Peptide Hormones / biosynthesis
  • Peptide Hormones / genetics
  • Recombinant Proteins / pharmacology
  • Smad Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism*


  • Bone Morphogenetic Proteins
  • Erfe protein, human
  • GDF11 protein, human
  • Gdf11 protein, mouse
  • Growth Differentiation Factors
  • HAMP protein, human
  • Hamp protein, mouse
  • Hepcidins
  • Peptide Hormones
  • Recombinant Proteins
  • Smad Proteins
  • Erythropoietin
  • SMURF1 protein, human
  • Smurf1 protein, mouse
  • Ubiquitin-Protein Ligases