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.
Cellular signalling. 2016 May 18 [Epub ahead of print]
José M Muñoz-Félix, Cristina Cuesta, Nuria Perretta-Tejedor, Mariela Subileau, Francisco J López-Hernández, José M López-Novoa, Carlos Martínez-Salgado
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 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 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., Inserm, U1036, CEA, DSV, Irtsv, Laboratoire Biologie du Cancer et de l'Infection, Université Joseph Fourier, Grenoble, F-38054, France., 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., 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 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: .