title: TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8.
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.
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Anita I R
authors: AI
authors: Spanjer
authors: Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, Germany;
authors: Hoeke A
authors: HA
authors: Baarsma
authors: Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, Germany;
authors: Lisette M
authors: LM
authors: Oostenbrink
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Sepp R
authors: SR
authors: Jansen
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Christine C
authors: CC
authors: Kuipers
authors: Asklepios Fachkliniken München-Gauting, Munich, Germany; and.
authors: Michael
authors: M
authors: Lindner
authors: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology.
authors: Dirkje S
authors: DS
authors: Postma
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Herman
authors: H
authors: Meurs
authors: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, and.
authors: Irene H
authors: IH
authors: Heijink
authors: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands r.gosens@rug.nl.
authors: Reinoud
authors: R
authors: Gosens
authors: Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, Germany; melanie.koenigshoff@hemholtz-muenchen.de.
authors: Melanie
authors: M
authors: Königshoff
mesh_terms: D000818:Animals; D002460:Cell Line; D005109:Extracellular Matrix; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008168:Lung / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000494:pharmacology; D000071818:Wnt-5a Protein / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C529739:Fzd8 protein, human; C497790:SMAD3 protein, human; C435831:WNT5B protein, human; C511610:Fzd8 protein, mouse
keywords: WNT signaling; airway remodeling; extracellular matrix; myofibroblast differentiation