title: Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
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.
authors.affiliation: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.forename: Chetana
authors.initials: C
authors.lastname: Sachidanandan
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Donna Y
authors.initials: DY
authors.lastname: Deng
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Hoyng
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D064451:Hepcidins; D007501:Iron / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; D054852:Small Molecule Libraries; C516138:dorsomorphin; D007501:Iron; D052005:Bone Morphogenetic Protein Receptors, Type I