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

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-beta1, 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-beta1 induced FZD8 specifically via Smad3-dependent signaling in MRC-5 and primary human lung fibroblasts. It is noteworthy that FZD8 knockdown reduced TGF-beta1-induced collagen Ialpha1, fibronectin, versican, alpha-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-beta1-induced gene expression in vitro, noncanonical WNT-5B mimicked TGF-beta1-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.-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., Konigshoff, M. TGF-beta-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8.

• 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.
• Konigshoff, M.