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Nat Chem Biol. 2008 Jan;4(1):33-41. Epub 2007 Nov 18.

Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.

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  • 1Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.

Abstract

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.

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PMID:
18026094
[PubMed - indexed for MEDLINE]
PMCID:
PMC2727650
Free PMC Article

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