TY - JOUR
T1 - Activation of WNT/beta-Catenin Signaling in Pulmonary Fibroblasts by TGF-beta(1) Is Increased in Chronic Obstructive Pulmonary Disease
AU - Baarsma, Hoeke A.
AU - Spanjer, Anita I. R.
AU - Haitsma, Gertruud
AU - Engelbertink, Lilian H. J. M.
AU - Meurs, Herman
AU - Jonker, Marnix R.
AU - Timens, Wim
AU - Postma, Dirkje S.
AU - Kerstjens, Huib A. M.
AU - Gosens, Reinoud
PY - 2011/9/30
Y1 - 2011/9/30
N2 - Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/beta-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 beta-catenin in fibroblast phenotype and function.Methods: We assessed the expression of WNT-pathway genes and the functional role of beta-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-beta(1), a growth factor important in COPD pathogenesis, induced WNT-5B, FZD(8), DVL3 and beta-catenin mRNA expression. The induction of WNT-5B, FZD(6), FZD(8) and DVL3 mRNA by TGF-beta(1) was higher in fibroblasts of individuals with COPD than without COPD, whilst basal expression was similar. Accordingly, TGF-beta(1) activated beta-catenin signaling, as shown by an increase in transcriptionally active and total beta-catenin protein expression. Furthermore, TGF-beta(1) induced the expression of collagen1 alpha 1, alpha-sm-actin and fibronectin, which was attenuated by beta-catenin specific siRNA and by pharmacological inhibition of beta-catenin, whereas the TGF-beta(1)-induced expression of PAI-1 was not affected. The induction of transcriptionally active beta-catenin and subsequent fibronectin deposition induced by TGF-beta(1) were enhanced in pulmonary fibroblasts from individuals with COPD.Conclusions: beta-catenin signaling contributes to ECM production by pulmonary fibroblasts and contributes to myofibroblasts differentiation. WNT/beta-catenin pathway expression and activation by TGF-beta(1) is enhanced in pulmonary fibroblasts from individuals with COPD. This suggests an important role of the WNT/beta-catenin pathway in regulating fibroblast phenotype and function in COPD.
AB - Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/beta-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 beta-catenin in fibroblast phenotype and function.Methods: We assessed the expression of WNT-pathway genes and the functional role of beta-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-beta(1), a growth factor important in COPD pathogenesis, induced WNT-5B, FZD(8), DVL3 and beta-catenin mRNA expression. The induction of WNT-5B, FZD(6), FZD(8) and DVL3 mRNA by TGF-beta(1) was higher in fibroblasts of individuals with COPD than without COPD, whilst basal expression was similar. Accordingly, TGF-beta(1) activated beta-catenin signaling, as shown by an increase in transcriptionally active and total beta-catenin protein expression. Furthermore, TGF-beta(1) induced the expression of collagen1 alpha 1, alpha-sm-actin and fibronectin, which was attenuated by beta-catenin specific siRNA and by pharmacological inhibition of beta-catenin, whereas the TGF-beta(1)-induced expression of PAI-1 was not affected. The induction of transcriptionally active beta-catenin and subsequent fibronectin deposition induced by TGF-beta(1) were enhanced in pulmonary fibroblasts from individuals with COPD.Conclusions: beta-catenin signaling contributes to ECM production by pulmonary fibroblasts and contributes to myofibroblasts differentiation. WNT/beta-catenin pathway expression and activation by TGF-beta(1) is enhanced in pulmonary fibroblasts from individuals with COPD. This suggests an important role of the WNT/beta-catenin pathway in regulating fibroblast phenotype and function in COPD.
KW - ENDOTHELIAL GROWTH-FACTOR
KW - AIRWAY SMOOTH-MUSCLE
KW - BETA-CATENIN
KW - TGF-BETA
KW - TRANSCRIPTIONAL ACTIVATION
KW - LUNG FIBROBLASTS
KW - GENE-EXPRESSION
KW - WNT PATHWAY
KW - FIBROSIS
KW - CELLS
U2 - 10.1371/journal.pone.0025450
DO - 10.1371/journal.pone.0025450
M3 - Article
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - 25450
ER -