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- Title
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
- Authors
Yu, Paul B; Hong, Charles C; Sachidanandan, Chetana; Babitt, Jodie L; Deng, Donna Y; Hoyng, Stefan A; Lin, Herbert Y; Bloch, Kenneth D; Peterson, Randall T
- 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.
- Publication
Nature chemical biology, 2008, Vol 4, Issue 1, p33
- ISSN
1552-4469
- Publication type
Journal Article
- DOI
10.1038/nchembio.2007.54