Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β₁ is increased in chronic obstructive pulmonary disease

PLoS One. 2011;6(9):e25450. doi: 10.1371/journal.pone.0025450. Epub 2011 Sep 30.


Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/β-catenin pathway has been associated with abnormal ECM turnover in various chronic diseases. We determined WNT-pathway gene expression in pulmonary fibroblasts of individuals with and without COPD and disentangled the role of β-catenin in fibroblast phenotype and function.

Methods: We assessed the expression of WNT-pathway genes and the functional role of β-catenin, using MRC-5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD.

Results: Pulmonary fibroblasts expressed mRNA of genes required for WNT signaling. Stimulation of fibroblasts with TGF-β₁, a growth factor important in COPD pathogenesis, induced WNT-5B, FZD₈, DVL3 and β-catenin mRNA expression. The induction of WNT-5B, FZD₆, FZD₈ and DVL3 mRNA by TGF-β₁ was higher in fibroblasts of individuals with COPD than without COPD, whilst basal expression was similar. Accordingly, TGF-β₁ activated β-catenin signaling, as shown by an increase in transcriptionally active and total β-catenin protein expression. Furthermore, TGF-β₁induced the expression of collagen1α1, α-sm-actin and fibronectin, which was attenuated by β-catenin specific siRNA and by pharmacological inhibition of β-catenin, whereas the TGF-β₁-induced expression of PAI-1 was not affected. The induction of transcriptionally active β-catenin and subsequent fibronectin deposition induced by TGF-β₁ were enhanced in pulmonary fibroblasts from individuals with COPD.

Conclusions: β-catenin signaling contributes to ECM production by pulmonary fibroblasts and contributes to myofibroblasts differentiation. WNT/β-catenin pathway expression and activation by TGF-β₁ is enhanced in pulmonary fibroblasts from individuals with COPD. This suggests an important role of the WNT/β-catenin pathway in regulating fibroblast phenotype and function in COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Case-Control Studies
  • Cell Differentiation / drug effects
  • Cell Line
  • Dishevelled Proteins
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibronectins / metabolism
  • Frizzled Receptors / genetics
  • Gene Expression Regulation / drug effects
  • Humans
  • Lung / pathology*
  • Male
  • Middle Aged
  • Myofibroblasts / cytology
  • Myofibroblasts / drug effects
  • Myofibroblasts / pathology
  • Phenotype
  • Phosphoproteins / genetics
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • Signal Transduction / drug effects*
  • Transforming Growth Factor beta1 / pharmacology*
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • DVL3 protein, human
  • Dishevelled Proteins
  • Fibronectins
  • Frizzled Receptors
  • Phosphoproteins
  • Transforming Growth Factor beta1
  • Wnt Proteins
  • beta Catenin