Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82.

Authors:
Robert Lafyatis
Robert Lafyatis
Boston University School of Medicine
United States
Julio C Mantero
Julio C Mantero
Arthritis Center
Jessica Gordon
Jessica Gordon
Hospital for Special Surgery
United States
Mary Carns
Mary Carns
Northwestern University Feinberg School of Medicine
Chicago | United States
Howard Dittrich
Howard Dittrich
University of Iowa Carver College of Medicine Cardiovascular Research Center
Iowa City | United States
Robert Spiera
Robert Spiera
Hospital for Special Surgery
New York | United States
Robert W Simms
Robert W Simms
Boston University School of Medicine
United States

J Invest Dermatol 2017 Dec 12;137(12):2473-2483. Epub 2017 Aug 12.

Rheumatology Division, Feinberg School of Medicine, Chicago, Illinois, USA.

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 the protein CBP with β-Catenin and inhibiting Wnt-activated genes. We used a 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 with 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 up-regulated 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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http://dx.doi.org/10.1016/j.jid.2017.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701831PMC
December 2017
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