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 language | English (US) |
|---|---|
| Pages (from-to) | 2473-2483 |
| Number of pages | 11 |
| Journal | Journal of Investigative Dermatology |
| Volume | 137 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2017 |
Funding
Funding for this work was provided by PRISM Biolab. The work in this article was also supported by National Institutes of Arthritis Musculoskeletal and Skin Disease grants: Scleroderma Center of Research Translation (1P50AR060780) to RL and Department of Defense Award (PR110276) to JV and RL. There was no change in MRSS or local skin score from baseline to 4 weeks in either placebo- or C-82–treated arms. Local skin score is not likely a sensitive measure for change of skin disease and has not been previously validated for such a purpose. Other measures such as ultrasonography or durometry might be more sensitive to change and should be compared with gene expression and local skin score as outcomes in future studies of local skin disease (Kissin et al., 2006). The lack of treatment effect on fibrotic gene expression or clinical measures of skin fibrosis is likely to reflect the short duration of the trial. Considering the postulated effect of C-82 blockade of β-catenin signaling of diverting mesenchymal cells from a profibrotic to an adipogenic phenotype within the fibrotic skin, a longer duration of treatment might be required to affect fibrosis. However, the alterations in gene expression associated with C-82 treatment signaling provide a strong surrogate for a likely clinical effect on fibrosis if drug treatment is extended. This is supported by the inverse correlation of these genes with the MRSS, indicating that many of the up-regulated genes are biomarkers for SSc skin disease. It is also supported by the trend, albeit weak, toward decreased expression of genes previously described to be markers for TGF-β–regulated fibrotic disease, THBS1 and COMP. Thus, we would anticipate that Wnts and/or their signaling pathway therapeutics require longer-duration treatment to see clinical effects on fibrosis. RL has received consulting fees from PRISM Biolab, Merck, Bristol Myers Squibb, Biocon, Formation, Genentech/Roche, UCB, and Sanofi and grant support from Elpidera and Regeneron. HD has received consulting fees from PRISM Pharma Co., Ltd. The other authors state no conflict of interest.
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Dermatology
- Cell Biology
