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

Robert Lafyatis*, Julio C. Mantero, Jessica Gordon, Nina Kishore, Mary Carns, Howard Dittrich, Robert Spiera, Robert W. Simms, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2473-2483
Number of pages11
JournalJournal of Investigative Dermatology
Volume137
Issue number12
DOIs
StatePublished - Dec 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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