Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Blood. 2011 May 5;117(18):4915-23. doi: 10.1182/blood-2010-10-313064. Epub 2011 Mar 10.

Abstract

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / etiology*
  • Anemia / prevention & control*
  • Animals
  • Antimicrobial Cationic Peptides / metabolism
  • Bone Morphogenetic Protein Receptors, Type I / antagonists & inhibitors
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Carrier Proteins / pharmacology
  • Hematopoietic Stem Cells / drug effects
  • Hep G2 Cells
  • Hepcidins
  • Humans
  • Inflammation / complications*
  • Interleukin-6 / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Turpentine / toxicity
  • Zebrafish
  • Zebrafish Proteins / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • HAMP protein, human
  • Hamp protein, mouse
  • Hepcidins
  • IL6 protein, human
  • Interleukin-6
  • LDN 193189
  • Pyrazoles
  • Pyrimidines
  • Recombinant Proteins
  • Zebrafish Proteins
  • noggin protein
  • Bone Morphogenetic Protein Receptors, Type I
  • Turpentine