title: BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain.
abstract: Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase 1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma (1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood. We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells. Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state.
authors.affiliation: Biology of Cancer and Infection, INSERM, Grenoble, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bidart
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ricard
authors.forename: Sandrine
authors.initials: S
authors.lastname: Levet
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
authors.forename: Christine
authors.initials: C
authors.lastname: Mallet
authors.forename: Laurent
authors.initials: L
authors.lastname: David
authors.forename: Mariela
authors.initials: M
authors.lastname: Subileau
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tillet
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Sabine
authors.initials: S
authors.lastname: Bailly
mesh_terms: D000328:Adult; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000097:blood*; D055412:Growth Differentiation Factors / Q000096:biosynthesis* / Q000097:blood; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D043484:Proprotein Convertases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism
chemical_list: C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; D043484:Proprotein Convertases; D012697:Serine Endopeptidases