In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

Ken Maes, Elizabeta Nemeth, G. David Roodman, Alissa Huston, Flavia Esteve, Cesar Freytes, Natalie Callander, Eirini Katodritou, Lisa Tussing-Humphreys, Seth Rivera, Karin Vanderkerken, Alan Lichtenstein, Tomas Ganz

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.

Original languageEnglish (US)
Pages (from-to)3635-3644
Number of pages10
JournalBlood
Volume116
Issue number18
DOIs
StatePublished - Nov 4 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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