TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8

• Published in: The FASEB journal Vol. 30; no. 5; p. 1823
• Main Authors: Spanjer, Anita I R, Baarsma, Hoeke A, Oostenbrink, Lisette M, Jansen, Sepp R, Kuipers, Christine C, Lindner, Michael, Postma, Dirkje S, Meurs, Herman, Heijink, Irene H, Gosens, Reinoud, Königshoff, Melanie
• Format: Journal Article
• Language: English
• Published: United States 01.05.2016
• Subjects: Animals; Cell Line; Extracellular Matrix; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Lung - cytology; Mice; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - physiology; Smad3 Protein - genetics; Smad3 Protein - metabolism; Specific Pathogen-Free Organisms; Transforming Growth Factor beta1 - pharmacology; Wnt Proteins - pharmacology; Wnt-5a Protein - pharmacology; myofibroblast differentiation; WNT signaling; extracellular matrix; airway remodeling
• ISSN: 1530-6860
• DOI: 10.1096/fj.201500129

TGF-β is important in lung injury and remodeling processes. TGF-β and Wingless/integrase-1 (WNT) signaling are interconnected; however, the WNT ligand-receptor complexes involved are unknown. Thus, we aimed to identify Frizzled (FZD) receptors that mediate TGF-β-induced profibrotic signaling. MRC-5 and primary human lung fibroblasts were stimulated with TGF-β1, WNT-5A, or WNT-5B in the presence and absence of specific pathway inhibitors. Specific small interfering RNA was used to knock down FZD8. In vivo studies using bleomycin-induced lung fibrosis were performed in wild-type and FZD8-deficient mice. TGF-β1 induced FZD8 specifically via Smad3-dependent signaling in MRC-5 and primary human lung fibroblasts. It is noteworthy that FZD8 knockdown reduced TGF-β1-induced collagen Iα1, fibronectin, versican, α-smooth muscle (sm)-actin, and connective tissue growth factor. Moreover, bleomycin-induced lung fibrosis was attenuated in FZD8-deficient mice in vivo Although inhibition of canonical WNT signaling did not affect TGF-β1-induced gene expression in vitro, noncanonical WNT-5B mimicked TGF-β1-induced fibroblast activation. FZD8 knockdown reduced both WNT-5B-induced gene expression of fibronectin and α-sm-actin, as well as WNT-5B-induced changes in cellular impedance. Collectively, our findings demonstrate a role for FZD8 in TGF-β-induced profibrotic signaling and imply that WNT-5B may be the ligand for FZD8 in these responses.-Spanjer, A. I. R., Baarsma, H. A., Oostenbrink, L. M., Jansen, S. R., Kuipers, C. C., Lindner, M., Postma, D. S., Meurs, H., Heijink, I. H., Gosens, R., Königshoff, M. TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8.