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. 2016 May;30(5):1823-35.
doi: 10.1096/fj.201500129. Epub 2016 Feb 5.

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

Anita I R Spanjer  1 , Hoeke A Baarsma  2 , Lisette M Oostenbrink  2 , Sepp R Jansen  1 , Christine C Kuipers  1 , Michael Lindner  3 , Dirkje S Postma  4 , Herman Meurs  1 , Irene H Heijink  5 , Reinoud Gosens  6 , Melanie Königshoff  7
Affiliations

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

Anita I R Spanjer et al. FASEB J. 2016 May.

Abstract

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.

Keywords: WNT signaling; airway remodeling; extracellular matrix; myofibroblast differentiation.

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