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Research ArticleDrug Discovery and Translational Medicine

Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

Andrew J. Haak, Pei-Suen Tsou, Mohammad A. Amin, Jeffrey H. Ruth, Phillip Campbell, David A. Fox, Dinesh Khanna, Scott D. Larsen and Richard R. Neubig
Journal of Pharmacology and Experimental Therapeutics June 2014, 349 (3) 480-486; DOI: https://doi.org/10.1124/jpet.114.213520
Andrew J. Haak
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Pei-Suen Tsou
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Mohammad A. Amin
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Jeffrey H. Ruth
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Phillip Campbell
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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David A. Fox
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Dinesh Khanna
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Scott D. Larsen
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Richard R. Neubig
Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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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.).

  • dx.doi.org/10.1124/jpet.114.213520.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 3
1 Jun 2014
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Research ArticleDrug Discovery and Translational Medicine

Rho GTPase–Pathway Inhibitor Reduces Markers of Fibrosis

Andrew J. Haak, Pei-Suen Tsou, Mohammad A. Amin, Jeffrey H. Ruth, Phillip Campbell, David A. Fox, Dinesh Khanna, Scott D. Larsen and Richard R. Neubig
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 480-486; DOI: https://doi.org/10.1124/jpet.114.213520

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Research ArticleDrug Discovery and Translational Medicine

Rho GTPase–Pathway Inhibitor Reduces Markers of Fibrosis

Andrew J. Haak, Pei-Suen Tsou, Mohammad A. Amin, Jeffrey H. Ruth, Phillip Campbell, David A. Fox, Dinesh Khanna, Scott D. Larsen and Richard R. Neubig
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 480-486; DOI: https://doi.org/10.1124/jpet.114.213520
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