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    Inhibition of beta-catenin signaling in the skin rescues cutaneous adipogenesis in systemic sclerosis: a randomized, double blind, placebo-controlled trial of C-82.
    J Invest Dermatol 2017 Aug 11. Epub 2017 Aug 11.
    Rheumatology Division, Feinberg School of Medicine.
    Several studies have suggested that Wnts might contribute to skin fibrosis in systemic sclerosis (SSc) by affecting the differentiation of pluripotent dermal cells. We tested C-82, a therapeutic that inhibits canonical Wnt signaling by blocking the interaction of cAMP Response Element-Binding Protein with β-Catenin and inhibiting Wnt-activated genes. We utilized previously unreported trial design, formulating C-82 for topical application and conducting a placebo controlled, double-blinded clinical trial in which patients with diffuse cutaneous SSc were treated with C-82 or placebo on opposite forearms. C-82 compared to placebo treated forearms did not show any clinical effect. Skin biopsies performed before and after treatment showed a very weak trend toward improvement in the C-82 treated skin of biomarkers of local skin disease, THBS1 and COMP. However, on microarray analysis C-82 treatment strongly upregulated two clusters of genes that correlate negatively with the severity of SSc skin disease. These clusters are highly associated with metabolism and one gene, PLIN2, expressed only by sebocytes and subcutaneous fat cells. These changes in gene expression strongly support a role for Wnts in differentiation of pluripotent cells into profibrotic fibroblasts, and the potential for C-82 with longer treatment to promote fat regeneration in SSc skin.

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    Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
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    Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
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    Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
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