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Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?
dc.contributor.authorWei, Junen_US
dc.contributor.authorMelichian, Denisaen_US
dc.contributor.authorKomura, Kazuhiroen_US
dc.contributor.authorHinchcliff, Moniqueen_US
dc.contributor.authorLam, Anna P.en_US
dc.contributor.authorLafyatis, Roberten_US
dc.contributor.authorGottardi, Cara J.en_US
dc.contributor.authorMacDougald, Ormond A.en_US
dc.contributor.authorVarga, Johnen_US
dc.date.accessioned2011-11-10T15:32:21Z
dc.date.available2012-07-12T17:42:24Zen_US
dc.date.issued2011-06en_US
dc.identifier.citationWei, Jun; Melichian, Denisa; Komura, Kazuhiro; Hinchcliff, Monique; Lam, Anna P.; Lafyatis, Robert; Gottardi, Cara J.; MacDougald, Ormond A.; Varga, John (2011). "Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?." Arthritis & Rheumatism 63(6): 1707-1717. <http://hdl.handle.net/2027.42/86862>en_US
dc.identifier.issn0004-3591en_US
dc.identifier.issn1529-0131en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/86862
dc.description.abstractObjective 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.en_US
dc.publisherWiley Subscription Services, Inc., A Wiley Companyen_US
dc.titleCanonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?en_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelGeriatricsen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.peerreviewedPeer Revieweden_US
dc.contributor.affiliationumUniversity of Michigan, Ann Arboren_US
dc.contributor.affiliationotherNorthwestern University Feinberg School of Medicine, Chicago, Illinoisen_US
dc.contributor.affiliationotherBoston University School of Medicine, Boston, Massachusettsen_US
dc.contributor.affiliationotherSection of Rheumatology, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, IL 60611en_US
dc.identifier.pmid21370225en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/86862/1/30312_ftp.pdf
dc.identifier.doi10.1002/art.30312en_US
dc.identifier.sourceArthritis & Rheumatismen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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