β-Catenin signaling is required for TGF-β1-induced extracellular matrix production by airway smooth muscle cells

Baarsma HA, Menzen MH, Halayko AJ, Meurs H, Kerstjens HA, Gosens R. beta-Catenin signaling is required for TGF-beta(1)-induced extracellular matrix production by airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 301: L956-L965, 2011. First published September 9, 2011; doi: 10.1152/ajplung.00123.2011.-Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway remodeling with altered extracellular matrix (ECM) deposition. Transforming growth factor-beta(1) (TGF-beta(1)) is upregulated in asthma and COPD and contributes to tissue remodeling in the airways by driving ECM production by structural cells, including airway smooth muscle. In this study, we investigated the activation of beta-catenin signaling and its contribution to ECM production by airway smooth muscle cells in response to TGF-beta(1). Stimulation of airway smooth muscle cells with TGF-beta(1) resulted in a time-dependent increase of total and nonphosphorylated beta-catenin protein expression via induction of beta-catenin mRNA and inhibition of GSK-3. In addition, the TGF-beta(1)-induced beta-catenin activated TCF/LEF-dependent gene transcription, as determined by the beta-catenin sensitive TOP-flash luciferase reporter assay. Furthermore, TGF-beta(1) stimulation increased mRNA expression of collagen I alpha 1, fibronectin, versican, and PAI-1. Pharmacological inhibition of beta-catenin by PKF115-584 or down-regulation of beta-catenin expression by specific small interfering RNA (siRNA) substantially inhibited TGF-beta(1)-induced expression of the ECM genes. Fibronectin protein deposition by airway smooth muscle cells in response to TGF-beta(1) was also inhibited by PKF115-584 and beta-catenin siRNA. Moreover, transfection of airway smooth muscle cells with a nondegradable beta-catenin mutant (S33Y beta-catenin) was sufficient for inducing fibronectin protein expression. Collectively, these findings indicate that beta-catenin signaling is activated in response to TGF-beta(1) in airway smooth muscle cells, which is required and sufficient for the regulation of ECM protein production. Targeting beta-catenin-dependent gene transcription may therefore hold promise as a therapeutic intervention in airway remodeling in both asthma and COPD.