Low α(2)β(1) integrin function enhances the proliferation of fibroblasts from patients with idiopathic pulmonary fibrosis by activation of the β-catenin pathway.

TitleLow α(2)β(1) integrin function enhances the proliferation of fibroblasts from patients with idiopathic pulmonary fibrosis by activation of the β-catenin pathway.
Publication TypeJournal Article
Year of Publication2012
AuthorsXia H, Seeman J, Hong J, Hergert P, Bodem V, Jessurun J, Smith K, Nho R, Kahm J, Gaillard P, Henke C
JournalAm J Pathol
Volume181
Issue1
Pagination222-33
Date Published2012 Jul
ISSN1525-2191
Keywordsbeta Catenin, Cell Proliferation, Cells, Cultured, Collagen Type I, Enzyme Activation, Fibroblasts, Gene Knockdown Techniques, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Idiopathic Pulmonary Fibrosis, Integrin alpha2beta1, Integrin beta1, Phosphorylation, Protein Phosphatase 2, Signal Transduction
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable fibroproliferative disorder characterized by unrelenting proliferation of fibroblasts and their deposition of collagen within alveoli, resulting in permanently scarred, nonfunctional airspaces. Normally, polymerized collagen suppresses fibroblast proliferation and serves as a physiological restraint to limit fibroproliferation after tissue injury. The IPF fibroblast, however, is a pathologically altered cell that has acquired the capacity to elude the proliferation-suppressive effects of polymerized collagen. The mechanism for this phenomenon remains incompletely understood. Here, we demonstrate that expression of α(2)β(1) integrin, a major collagen receptor, is pathologically low in IPF fibroblasts interacting with polymerized collagen. Low integrin expression in IPF fibroblasts is associated with a failure to induce PP2A phosphatase activity, resulting in abnormally high levels of phosphorylated (inactive) GSK-3β and high levels of active β-catenin in the nucleus. Knockdown of β-catenin in IPF fibroblasts inhibits their ability to proliferate on collagen. Interdiction of α(2)β(1) integrin in control fibroblasts reproduces the IPF phenotype and leads to the inability of these cells to activate PP2A, resulting in high levels of phosphorylated GSK-3β and active β-catenin and in enhanced proliferation on collagen. Our findings indicate that the IPF fibroblast phenotype is characterized by low α(2)β(1) integrin expression, resulting in a failure of integrin to activate PP2A phosphatase, which permits inappropriate activation of the β-catenin pathway.

DOI10.1016/j.ajpath.2012.03.034
Alternate JournalAm J Pathol
PubMed ID22642910
Grant ListP01-HL91775 / HL / NHLBI NIH HHS / United States
R01-HL074882 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Jose Jessurun, M.D.

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