title: Fibroblast adhesion results in the induction of a matrix remodeling gene expression program.
abstract: Fibrosis is believed to occur through the failure to terminate the normal tissue remodeling program. Tissue repair intimately involves the ability of fibroblasts to attach to extracellular matrix (ECM), resulting in cell migration and ECM contraction. Elevated, activated adhesive signaling is a key phenotypic hallmark of fibrotic cells. The precise contribution of adhesion to tissue remodeling and repair and fibrotic responses in fibroblasts is unclear, but involves focal adhesion kinase (FAK). FAK signals downstream of integrin-mediates attachment of fibroblasts to extracellular matrix. In this report, we show that FAK is required for the expression of a cohort of mRNAs encoding ECM and matrix remodeling genes including CCN2, alpha-smooth muscle actin (SMA) and type I collagen. Adhesion of fibroblasts to fibronectin, a component of the provisional matrix deposited in the initial phases of tissue repair, also resulted in the induction of CCN2, alpha-SMA and type I collagen mRNAs. Endothelin-1 (ET-1), a key inducer of pro-fibrotic gene expression, was also induced upon fibroblast attachment to ECM, and antagonism of the ET-1 receptors significantly reduced the ability of adhesion to induce expression of CCN2, alpha-SMA and type I collagen mRNAs. These results suggest that adhesion of fibroblasts to matrix during the initial phases of tissue remodeling and repair may actively contribute to the tissue repair program through the induction of pro-fibrotic gene expression.
authors.affiliation: CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Dental Sciences Building, University of Western Ontario, London ON, Canada N6A 5C1.
authors.forename: Laura
authors.initials: L
authors.lastname: Kennedy
authors.forename: Xu
authors.initials: X
authors.lastname: Shi-Wen
authors.forename: David E
authors.initials: DE
authors.lastname: Carter
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D005353:Fibronectins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse