title: Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro.
abstract: Upregulated synthesis of extracellular matrix (ECM) proteins by myofibroblasts is a common phenomenon in the development of fibrosis. Although the role of TGF-β in fibrosis development has been extensively studied, the involvement of other members of this superfamily of cytokines, the bone morphogenetic proteins (BMPs) in organ fibrosis has given contradictory results. BMP9 is the main ligand for activin receptor-like kinase-1 (ALK1) TGF-β1 type I receptor and its effect on fibrosis development is unknown. Our purpose was to study the effect of BMP9 in ECM protein synthesis in fibroblasts, as well as the involved receptors and signaling pathways. In cultured mice fibroblasts, BMP9 induces an increase in collagen, fibronectin and connective tissue growth factor expression, associated with Smad1/5/8, Smad2/3 and Erk1/2 activation. ALK5 inhibition with SB431542 or ALK1/2/3/6 with dorsomorphin-1, inhibition of Smad3 activation with SIS3, and inhibition of the MAPK/Erk1/2 with U0126, demonstrates the involvement of these pathways in BMP9-induced ECM synthesis in MEFs. Whereas BMP9 induced Smad1/5/8 phosphorylation through ALK1, it also induces Smad2/3 phosphorylation through ALK5 but only in the presence of ALK1. Summarizing, this is the first study that accurately identifies BMP9 as a profibrotic factor in fibroblasts that promotes ECM protein expression through ALK1 and ALK5 receptors.
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Muñoz-Félix
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cuesta
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Perretta-Tejedor
authors.affiliation: Inserm, U1036, CEA, DSV, Irtsv, Laboratoire Biologie du Cancer et de l'Infection, Université Joseph Fourier, Grenoble, F-38054, France.
authors.forename: Mariela
authors.initials: M
authors.lastname: Subileau
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Hernández
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Hospital Universitario de Salamanca, Salamanca, Spain. Electronic address: carlosms@usal.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Salgado
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D055427:Growth Differentiation Factor 2 / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D014176:Protein Biosynthesis; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D055427:Growth Differentiation Factor 2; D051785:Smad Proteins; D030201:Activin Receptors, Type I
keywords: ALK1; ALK5; BMP9; Extracellular matrix proteins; Fibroblasts; Fibrosis