Yu, P. B. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4, 33-41

Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Nature Chemical Biology (Impact Factor: 13). 11/2007; 4(1):33-41. DOI: 10.1038/nchembio.2007.54


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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Available from: Stefan A Hoyng, Apr 14, 2014
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    • "RESEARCH ARTICLE Development (2015) 142, 2352-2363 doi:10.1242/dev.118679 DEVELOPMENT In HAECs, BMP inhibition was achieved through chronic treatment with recombinant Noggin protein, a potent secreted BMP antagonist, or with the pharmacological BMP pathway inhibitor dorsomorphin (Yu et al., 2008). We first verified that Noggin could suppress BMP-induced SMAD1/5 phosphorylation and nuclear translocation (supplementary material Fig. S3A,B). "
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    • "Interestingly, functional studies in the direct developing hemichordate S. kowalevskii, echinoderms, and our results in P. flava show that regardless of the source of bmp2/4 expression, the activity of the Bmp pathway in all studied ambulacrarians is always confined to the dorsal ectoderm where it is responsible for the specification of dorsal fates (Duboc et al., 2004; Lapraz et al., 2009b; Lowe et al., 2006). Our attempts to inhibit Bmp signaling using dorsomorphin (Hao et al., 2008; Yu et al., 2008) or Noggin (Bayramov et al., 2011) did not affect either the development of P. flava, nor caused any noticeable changes of pSmad1/5 activation (data not shown). Nonetheless, taken together our above-described results strongly suggest that Bmp signaling is involved in patterning dorsal structures during P. flava development. "
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    • "As was the case for FGF2, these FGF9-mediated processes were inhibited by noggin, demonstrating a similar requirement for endogenous BMP signaling. Normalized to total ERK, fold activation of ERK in response to FGF9 dropped from 3.3× (±0.6) in the Next we inhibited BMP signaling at the level of BMP receptors using dorsomorphin, a selective small-molecule inhibitor of ligand-activated type I BMP receptors (BMPRs; Yu et al., 2008; Kamaid et al., 2010). We confirmed that a 30-min preincubation with 5 μM dorsomorphin completely blocked BMP4 from activating its downstream effectors Smad1/5 in DCDMLs but did not FIGURE 1: "
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