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.
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.
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.).
Andrew J
AJ
Haak
Pei-Suen
PS
Tsou
Mohammad A
MA
Amin
Jeffrey H
JH
Ruth
Phillip
P
Campbell
David A
DA
Fox
Dinesh
D
Khanna
Scott D
SD
Larsen
Richard R
RR
Neubig
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D026362:Serum Response Factor / Q000235:genetics*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526317:CCN2 protein, human; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D008246:Lysophospholipids; C431575:MRTFA protein, human; C000589288:N-(4-chlorophenyl)-1-((3-(furan-2-yl)phenyl)carbonyl)piperidine-3-carboxamide; D009557:Nipecotic Acids; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C032881:lysophosphatidic acid