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Abstract Number: 2929

WNT5A Promotes Tissue Fibrosis By Wnt/PCP-Dependent Activation of Latent TGF-β

Chih-Wei Chen1, Thuong Trinh-Minh2, Neng-Yu Lin2, Yun Zhang3, Florian Groeber4, Christian Beyer5, Georg Schett6 and Jörg Distler7, 1Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, Erlangen, Germany, 2Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 3Department of Internal Medicine 3 and Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 4Translational Center Würzburg, Fraunhofer Ins. IGB, Würzburg, Germany, 5Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 6Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany., Erlangen, Germany, 7Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: fibrosis, Integrins, systemic sclerosis and transforming growth factor, WNT Signaling

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Session Information

Date: Wednesday, November 8, 2017

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics II

Session Type: ACR Concurrent Abstract Session

Session Time: 9:00AM-10:30AM

Background/Purpose:  Canonical Wnt/β-catenin signaling has emerged as a core pathway of fibrosis. They role of non-canonical Wnt signaling, however, has not been systematically studied. In this study we aimed to characterize the role of non-canonical WNT signaling in the pathogenesis of fibrotic diseases such as systemic sclerosis (SSc).

Methods:  The expression of Wnt ligands was analyzed in patients with SSc, idiopathic pulmonary fibrosis (IPF) and sclerodermatous chronic graft-versus-host disease (cGvHD). The functional role of non-canonical WNT signaling was evaluated in full thickness skin grafts, in bleomycin-induced fibrosis and in experimental cGvHD. WNT signaling was modulated in vitro and in vivo using small molecule inhibitors, siRNA mediated knockdown, fibroblasts specific recombination and soluble decoy receptors.

Results:

Profiling of all non-canonical WNT ligands demonstrated that WNT5A is the predominant non-canonical Wnt ligand in skin and lungs with pronounced overexpression in patients with SSc, IPF and cGvHD as compared to non-fibrotic controls. WNT5A induced fibroblast-to-myofibroblast transition and collagen release in conventional cell culture and in full-thickness skin models in vitro and was sufficient to induce dermal and pulmonary fibrosis in vivo. Fibroblast-specific knockout of Wnt5a ameliorated bleomycin-induced fibrosis and experimental cGvHD. The profibrotic effects of WNT5A were independent of canonical Wnt signaling and of WNT/Calcium signaling, but were mediated by the planar cell polarity pathway (PCP). Genetic or pharmacologic inactivation of JNK or of cJUN abrogated the profibrotic effects of WNT5A. Further profiling revealed that WNT5A activates ROR2 and RYK receptors and that RAC1, RHOA and PI3K are essential further signaling intermediates. Of note, WNT5A stimulation also induced SMAD3 phosphorylation within 10 min in a PCP-dependent manner. SMAD3 phosphorylation was not mediated by JNK-dependent transphosphorylation of SMAD3 or dependent on transactivation of TGF-β receptor by RYK, but induced by a rapid increase in the fraction of active, but not of total TGF-β. Activation of latent TGF-β by WNT5A/PCP signaling required MMPs, thrombospondin-1(TSP-1) and integrin αV, but not ROS generation. Inactivation of MMPs, TSP-1 or integrin αV prevented WNT5A induced SMAD3 phosphorylation and ameliorated WNT5A-induced fibroblast activation.

Conclusion: We characterize WNT5A-induced PCP signaling as a novel pro-fibrotic mediator in fibrotic diseases. WNT5A contributes to the increased activation of TGF-β signaling in fibrotic diseases. We also provide evidence that WNT5A/PCP signaling may be a potential target for therapeutic intervention in fibrotic diseases.


Disclosure: C. W. Chen, None; T. Trinh-Minh, None; N. Y. Lin, None; Y. Zhang, None; F. Groeber, None; C. Beyer, None; G. Schett, None; J. Distler, 4D Science, 1,Anamar Medical, Active Biotech, Array Biopma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis, UCB, 2,Actelion Pharmaceuticals US, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi, UCB, 5.

To cite this abstract in AMA style:

Chen CW, Trinh-Minh T, Lin NY, Zhang Y, Groeber F, Beyer C, Schett G, Distler J. WNT5A Promotes Tissue Fibrosis By Wnt/PCP-Dependent Activation of Latent TGF-β [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/wnt5a-promotes-tissue-fibrosis-by-wntpcp-dependent-activation-of-latent-tgf-%ce%b2/. Accessed February 6, 2023.
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