Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?
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OBJECTIVE: Because aberrant Wnt signaling has been linked with systemic sclerosis (SSc) and pulmonary fibrosis, we sought to investigate the effect of Wnt-10b on skin homeostasis and differentiation in transgenic mice and in explanted mesenchymal cells. METHODS: The expression of Wnt-10b in patients with SSc and in a mouse model of fibrosis was investigated. The skin phenotype and biochemical characteristics of Wnt-10b-transgenic mice were evaluated. The in vitro effects of ectopic Wnt-10b were examined in explanted skin fibroblasts and preadipocytes. RESULTS: The expression of Wnt-10b was increased in lesional skin biopsy specimens from patients with SSc and in those obtained from mice with bleomycin-induced fibrosis. Transgenic mice expressing Wnt-10b showed progressive loss of subcutaneous adipose tissue accompanied by dermal fibrosis, increased collagen deposition, fibroblast activation, and myofibroblast accumulation. Wnt activity correlated with collagen gene expression in these biopsy specimens. Explanted skin fibroblasts from transgenic mice demonstrated persistent Wnt/β-catenin signaling and elevated collagen and α-smooth muscle actin gene expression. Wnt-10b infection of normal fibroblasts and preadipocytes resulted in blockade of adipogenesis and transforming growth factor β (TGFβ)-independent up-regulation of fibrotic gene expression. CONCLUSION: SSc is associated with increased Wnt-10b expression in the skin. Ectopic Wnt-10b causes loss of subcutaneous adipose tissue and TGFβ-independent dermal fibrosis in transgenic mice. These findings suggest that Wnt-10b switches differentiation of mesenchymal cells toward myofibroblasts by inducing a fibrogenic transcriptional program while suppressing adipogenesis. Wnt-10b-transgenic mice represent a novel animal model for investigating Wnt signaling in the setting of fibrosis.
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In vitro, FIZZ1 suppresses adipogenesis and stimulates myofibroblast differentiation via Notch1 signaling.
“In vitro, FIZZ1 suppresses adipogenesis and stimulates myofibroblast differentiation via Notch1 signaling.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [89]
Adipocyte to myofibroblast transition is strongly driven by TGFβ, FIZZ1, and possibly Wnt signaling.
“Adipocyte to myofibroblast transition is strongly driven by TGFβ (88), Found in inflammatory zone 1 (FIZZ1) and possibly Wnt signaling (89).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [89]
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- Authors
- Wei, J., Melichian, D., Komura, K., Hinchcliff, M., Lam, A. P., Lafyatis, R., Gottardi, C. J., MacDougald, O. A., & Varga, J.
- Affiliations
- Northwestern University (US)
- Boston University (US)
- University of Michigan (US)
- ORCID
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2011-05-31
- Volume
- 63
- Issue
- 6
- Pages
- 1707-1717
- ISSN
- 0004-3591 (ISSN-L)
- PMC
- PMC3124699
- OpenAlex
- W1967131493
- Cited by
- 214
- References
- 52
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 12 · 2023: 6 · 2022: 8 · 2021: 18 · 2020: 12 · 2019: 14 · 2018: 13 · 2017: 22 · 2016: 23 · 2015: 18 · 2014: 13 · 2013: 16 · 2012: 23
- FWCI
- 13.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P30HL101292, R01HL094643, K08HL093216)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK062876, DK-51563, N02 DK062876, R01DK051563, R01DK062876)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR49025, R01AR051089, R01AR049025)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Keywords
- Wnt signaling, systemic sclerosis, skin fibrosis, myofibroblast differentiation, adipogenesis, collagen deposition, Wnt/β-catenin signaling, bleomycin-induced fibrosis, transgenic mouse model, dermal fibroblasts, preadipocytes
- MeSH terms
- Actins, Animals, Bleomycin, Collagen, Disease Models, Animal, Female, Fibroblasts, Fibrosis, Humans, Lipodystrophy, Mice, Transgenic, Scleroderma, Systemic, Skin, Gene Expression, Cell Culture Techniques, Adipogenesis, Wnt Proteins, beta Catenin, Mice, Myofibroblasts
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