by Hoeke A. Baarsma, Anita I. R. Spanjer, Gertruud Haitsma, Lilian H. J. M. Engelbertink, Herman Meurs, Marnix R. Jonker, Wim Timens, Dirkje S. Postma, Huib A. M. Kerstjens, Reinoud Gosens
Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/ß-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 ß-catenin in fibroblast phenotype and function. Methods
We assessed the expression of WNT-pathway genes and the functional role of ß-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-ß1, a growth factor important in COPD pathogenesis, induced WNT-5B, FZD8, DVL3 and ß-catenin mRNA expression. The induction of WNT-5B, FZD6, FZD8 and DVL3 mRNA by TGF-ß1 was higher in fibroblasts of individuals with COPD than without COPD, whilst basal expression was similar. Accordingly, TGF-ß1 activated ß-catenin signaling, as shown by an increase in transcriptionally active and total ß-catenin protein expression. Furthermore, TGF-ß1 induced the expression of collagen1a1, a-sm-actin and fibronectin, which was attenuated by ß-catenin specific siRNA and by pharmacological inhibition of ß-catenin, whereas the TGF-ß1-induced expression of PAI-1 was not affected. The induction of transcriptionally active ß-catenin and subsequent fibronectin deposition induced by TGF-ß1 were enhanced in pulmonary fibroblasts from individuals with COPD. Conclusions
ß-catenin signaling contributes to ECM production by pulmonary fibroblasts and contributes to myofibroblasts differentiation. WNT/ß-catenin pathway expression and activation by TGF-ß1 is enhanced in pulmonary fibroblasts from individuals with COPD. This suggests an important role of the WNT/ß-catenin pathway in regulating fibroblast phenotype and function in COPD.