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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Extracellular Matrix
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Lung / cytology
  • Mice
  • Mice, Knockout
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / 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


  • Fzd8 protein, human
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • WNT5B protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • frizzled 8 protein, mouse