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β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis
Open accessAbstract
Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis.Methods Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4',6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis.Results The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis.Conclusions The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.
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“TGFβ signaling via p38 MAPK lowers dickkopf-1 (DKK1) expression (62), which is an inhibitor of canonical Wnt signaling via β-catenin. In skin and fibroblasts of SSc patients, decreased DKK1 expression is observed (62), together with increased β-catenin accumulation (63), and increased expression of Wnt signaling-related genes (62, 64).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [63]
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Metadata
- Authors
- Beyer, C., Schramm, A., Akhmetshina, A., Dees, C., Kireva, T., Gelse, K., Sonnylal, S., de Crombrugghe, B., Taketo, M. M., Distler, O., Schett, G., & Distler, J. H. W.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- The University of Texas MD Anderson Cancer Center (US)
- Kyoto University (JP)
- University of Zurich (CH)
- Corresponding author
- Distler, Jörg H W
- ORCID
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 71
- Issue
- 5
- Pages
- 761-767
- ISSN
- 0003-4967 (ISSN-L)
- PMC
- PMC3951949
- OpenAlex
- W2106544674
- Cited by
- 203
- References
- 35
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 13 · 2017: 23 · 2016: 26 · 2015: 13 · 2014: 14 · 2013: 16 · 2012: 12
- FWCI
- 12.71
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health (5p50ar054144-05)
- Japan Society for the Promotion of Science (21229005)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50-AR-054144)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Keywords
- β-catenin, Wnt signaling, systemic sclerosis, skin fibrosis, fibroblast activation, Wnt1, myofibroblast differentiation, bleomycin-induced fibrosis, Wnt inhibitors
- MeSH terms
- Adult, Aged, Cell Nucleus, Female, Fibroblasts, Fibrosis, Humans, Male, Middle Aged, Scleroderma, Systemic, Skin, Wnt Proteins, beta Catenin, Young Adult, Wnt Signaling Pathway
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