4-methylene-2-octyl-5-oxofuran-3-carboxylic-acid and dorsomorphin

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.

Topics: Animals; Antimicrobial Cationic Peptides; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Cell Differentiation; Cell Line, Tumor; Hepcidins; Iron; Mice; Mice, Inbred C57BL; Osteoblasts; Osteogenesis; Phosphorylation; Pyrazoles; Pyrimidines; Signal Transduction; Smad Proteins; Small Molecule Libraries; Transcription, Genetic; Zebrafish