PuSH - Publication Server of Helmholtz Zentrum München: TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8.

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Spanjer, A.I.* ; 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.

FASEB J. 30, 1823-1835 (2016)

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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.

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