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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 (2016): TGF-beta-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8. In: FASEB Journal, Vol. 30, No. 5: pp. 1823-1835
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Abstract

TGF-beta is important in lung injury and remodeling processes. TGF-beta 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-beta-induced profibrotic signaling. MRC-5 and primary human lung fibroblasts were stimulated with TGF-beta(1), 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 wildtype and FZD8-deficient mice. TGF-beta(1) induced FZD8 specifically via Smad3-dependent signaling in MRC-5 and primary human lung fibroblasts. It is noteworthy that FZD8 knockdown reduced TGF-beta(1)-induced collagen I alpha 1, fibronectin, versican, a-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-beta(1)-induced gene expression in vitro, noncanonical WNT-5B mimicked TGF-beta(1)-induced fibroblast activation. FZD8 knockdown reduced both WNT-5B-induced gene expression of fibronectin and alpha-sm-actin, as well as WNT-5B-induced changes in cellular impedance. Collectively, our findings demonstrate a role for FZD8 in TGF-beta-induced profibrotic signaling and imply that WNT-5B may be the ligand for FZD8 in these responses.