Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Nat Chem Biol. 2008 Jan;4(1):33-41. doi: 10.1038/nchembio.2007.54. Epub 2007 Nov 18.


Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling-dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6-stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.

Publication types

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

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Bone Morphogenetic Protein Receptors, Type I / antagonists & inhibitors
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Hepcidins
  • Iron / blood
  • Iron / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteogenesis / drug effects*
  • Phosphorylation
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Signal Transduction
  • Smad Proteins / metabolism
  • Small Molecule Libraries / pharmacology*
  • Transcription, Genetic / drug effects
  • Zebrafish* / embryology
  • Zebrafish* / metabolism


  • Antimicrobial Cationic Peptides
  • Bone Morphogenetic Proteins
  • Hamp protein, mouse
  • Hepcidins
  • Pyrazoles
  • Pyrimidines
  • Smad Proteins
  • Small Molecule Libraries
  • dorsomorphin
  • Iron
  • Bone Morphogenetic Protein Receptors, Type I

Associated data

  • PubChem-Substance/26740883
  • PubChem-Substance/26740884
  • PubChem-Substance/26740885