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.
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.
Authors: Raphael Lemaire; Giuseppina Farina; Julie Bayle; Michael Dimarzio; Sarah A Pendergrass; Ausra Milano; Bernard Perbal; Michael L Whitfield; Robert Lafyatis Journal: J Invest Dermatol Date: 2010-02-25 Impact factor: 8.551
Authors: Christina N Bennett; Kenneth A Longo; Wendy S Wright; Larry J Suva; Timothy F Lane; Kurt D Hankenson; Ormond A MacDougald Journal: Proc Natl Acad Sci U S A Date: 2005-02-22 Impact factor: 11.205
Authors: Kenneth A Longo; Wendy S Wright; Sona Kang; Isabelle Gerin; Shian-Huey Chiang; Peter C Lucas; Mark R Opp; Ormond A MacDougald Journal: J Biol Chem Date: 2004-06-09 Impact factor: 5.157
Authors: Yangyang Wang; Christian F Guerrero-Juarez; Yuchi Qiu; Huijing Du; Weitao Chen; Seth Figueroa; Maksim V Plikus; Qing Nie Journal: Exp Dermatol Date: 2019-04 Impact factor: 3.960