Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells
Open accessAbstract
OBJECTIVE: Fibrosis in human diseases and animal models is associated with aberrant Wnt/β-catenin pathway activation. The aim of this study was to characterize the regulation, activity, mechanism of action, and significance of Wnt/β-catenin signaling in the context of systemic sclerosis (SSc). METHODS: The expression of Wnt signaling pathway components in SSc skin biopsy specimens was analyzed. The regulation of profibrotic responses by canonical Wnt/β-catenin was examined in explanted human mesenchymal cells. Fibrotic responses were studied using proliferation, migration, and gel contraction assays. The cell fate specification of subcutaneous preadipocytes by canonical Wnt signaling was evaluated. RESULTS: Analysis of published genome-wide expression data revealed elevated expression of the Wnt receptor FZD2 and the Wnt target LEF1 and decreased expression of Wnt antagonists DKK2 and WIF1 in skin biopsy specimens from subsets of patients with diffuse cutaneous SSc compared to the other distinct subsets. Immunohistochemical analysis showed increased nuclear β-catenin expression in these biopsy specimens. In vitro, Wnt-3a induced β-catenin activation, stimulated fibroblast proliferation and migration, collagen gel contraction, and myofibroblast differentiation, and enhanced profibrotic gene expression. Genetic and pharmacologic approaches were used to demonstrate that these profibrotic responses involved autocrine transforming growth factor β signaling via Smads. In contrast, in explanted subcutaneous preadipocytes, Wnt-3a repressed adipogenesis and promoted myofibroblast differentiation. CONCLUSION: Canonical Wnt signaling was hyperactivated in SSc skin biopsy specimens. In explanted mesenchymal cells, Wnt-3a stimulated fibrogenic responses while suppressing adipogenesis. Taken together, these results indicate that Wnts have potent profibrotic effects, and that canonical Wnt signaling plays an important role in the pathogenesis of fibrosis and lipoatrophy in SSc.
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TGFβ signaling via p38 MAPK lowers DKK1 expression, an inhibitor of canonical Wnt signaling via β-catenin; SSc skin and fibroblasts show decreased DKK1, increased β-catenin accumulation, and increased Wnt-related gene expression.
“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 [64]
Wnt signaling can induce autocrine TGFβ signaling, and overexpression of DKK1 protects mice against TGFβ-receptor mediated skin fibrosis, indicating both pathways are interdependent.
“Notably, Wnt signaling can induce autocrine TGFβ signaling (64) and overexpression of DKK1 protects mice even against TGFβ-receptor mediated skin fibrosis, indicating that both pathways are closely interwoven and interdependent.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [64]
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- Authors
- Wei, J., Fang, F., Lam, A. P., Sargent, J. L., Hamburg, E., Hinchcliff, M. E., Gottardi, C. J., Atit, R., Whitfield, M. L., & Varga, J.
- Affiliations
- Northwestern University (US)
- Dartmouth College (US)
- Case Western Reserve University (US)
- ORCID
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2012-07-27
- Volume
- 64
- Issue
- 8
- Pages
- 2734-2745
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- PMC
- PMC3553791
- OpenAlex
- W2018185237
- Cited by
- 226
- References
- 52
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 10 · 2023: 11 · 2022: 17 · 2021: 29 · 2020: 24 · 2019: 18 · 2018: 18 · 2017: 21 · 2016: 13 · 2015: 13 · 2014: 15 · 2013: 15 · 2012: 8
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL094643, K08HL093216)
- National Institute of General Medical Sciences (T32GM007250)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 42309, R01AR042309, R56AR042309, R01AR049025)
- National Institute of Dental and Craniofacial Research (R01DE018470)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › 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
- Wnt/β-catenin signaling, systemic sclerosis, fibrosis, Smad signaling, TGF-beta, mesenchymal cells, fibroblast proliferation and migration, myofibroblast differentiation, adipogenesis, Wnt3a, FZD2, LEF1, DKK2, WIF1, lipoatrophy, skin biopsy
- MeSH terms
- Adult, Biopsy, Cell Movement, Cells, Cultured, Fibroblasts, Fibrosis, Humans, Mesoderm, Repressor Proteins, Scleroderma, Systemic, Skin, Signal Transduction, Case-Control Studies, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Cell Proliferation, Wnt Proteins, Frizzled Receptors, beta Catenin, Smad Proteins, Lymphoid Enhancer-Binding Factor 1, Wnt3A Protein
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