title: Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β₁ is increased in chronic obstructive pulmonary disease.
abstract: 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.
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. H.A.Baarsma@rug.nl
authors: Hoeke A
authors: HA
authors: Baarsma
authors: Anita I R
authors: AI
authors: Spanjer
authors: Gertruud
authors: G
authors: Haitsma
authors: Lilian H J M
authors: LH
authors: Engelbertink
authors: Herman
authors: H
authors: Meurs
authors: Marnix R
authors: MR
authors: Jonker
authors: Wim
authors: W
authors: Timens
authors: Dirkje S
authors: DS
authors: Postma
authors: Huib A M
authors: HA
authors: Kerstjens
authors: Reinoud
authors: R
authors: Gosens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000072261:Dishevelled Proteins; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D005353:Fibronectins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D051176:beta Catenin