Abstract
Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)–and serum response factor (SRF)–regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)–and transforming growth factor β (TGFβ)–stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.
Footnotes
- Received January 23, 2014.
- Accepted March 31, 2014.
A.J.H. and P.-S.T. contributed equally to this work.
This work was supported in part by a generous gift from Jon and Lisa Rye; National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant K24 AR063120-02] (to D.K.); and the Arthritis Foundation (to P.-S.T.).
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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