ALK1 heterozygosity increases extracellular matrix protein expression, proliferation and migration in fibroblasts.

Abstract

Fibrosis is a pathological situation in which excessive amounts of extracellular matrix (ECM) are deposited in the tissue. Myofibroblasts play a crucial role in the development and progress of fibrosis as they actively synthesize ECM components such as collagen I, fibronectin and connective tissue growth factor (CTGF) and cause organ fibrosis. Transforming growth factor beta 1 (TGF-β1) plays a major role in tissue fibrosis. Activin receptor-like kinase 1 (ALK1) is a type I receptor of TGF-β1 with an important role in angiogenesis whose function in cellular biology and TGF-β signaling is well known in endothelial cells, but its role in fibroblast biology and its contribution to fibrosis is poorly studied. We have recently demonstrated that ALK1 regulates ECM protein expression in a mouse model of obstructive nephropathy. Our aim was to evaluate the role of ALK1 in several processes involved in fibrosis such as ECM protein expression, proliferation and migration in ALK1(+/+) and ALK1(+/-) mouse embryonic fibroblasts (MEFs) after TGF-β1 stimulations and inhibitors. ALK1 heterozygous MEFs show increased expression of ECM proteins (collagen I, fibronectin and CTGF/CCN2), cell proliferation and migration due to an alteration of TGF-β/Smad signaling. ALK1 heterozygous disruption shows an increase of Smad2 and Smad3 phosphorylation that explains the increases in CTGF/CCN2, fibronectin and collagen I, proliferation and cell motility observed in these cells. Therefore, we suggest that ALK1 plays an important role in the regulation of ECM protein expression, proliferation and migration.

• Authors: José M Muñoz-Félix, Nuria Perretta-Tejedor, Nélida Eleno, José M López-Novoa, Carlos Martínez-Salgado
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1843 Issue 6 Pg. 1111-22 (Jun 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24594380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• CCN2 protein, mouse
• Collagen Type I
• Extracellular Matrix Proteins
• Fibronectins
• RNA, Messenger
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta
• Connective Tissue Growth Factor
• betaIG-H3 protein
• Activin Receptors, Type I
• Activin Receptors, Type II
• Acvrl1 protein, mouse

Topics

• Activin Receptors, Type I (physiology)
• Activin Receptors, Type II
• Animals
• Blotting, Western
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Collagen Type I (genetics, metabolism)
• Connective Tissue Growth Factor (genetics, metabolism)
• Embryo, Mammalian (cytology, metabolism)
• Extracellular Matrix Proteins (genetics, metabolism, pharmacology)
• Female
• Fibroblasts (cytology, metabolism)
• Fibronectins (genetics, metabolism)
• Fluorescent Antibody Technique
• Heterozygote
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphorylation
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Smad2 Protein (genetics, metabolism)
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta (pharmacology)
• Wound Healing