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Modulating myofibroblast transition in systemic sclerosis through inhibition of Rho/MRTF regulated transcription (1054.9)
Author(s) -
Haak Andrew,
Tsou PeiSuen,
Fox David,
Khanna Dinesh,
Larsen Scott,
Neubig Rick
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1054.9
Subject(s) - myofibroblast , ctgf , myocardin , transcription factor , cancer research , transforming growth factor , biology , connective tissue , microbiology and biotechnology , fibrosis , serum response factor , rhoa , scleroderma (fungus) , growth factor , receptor , gene , immunology , pathology , signal transduction , medicine , genetics , inoculation
Systemic sclerosis (SSc) or scleroderma, like many fibrotic disorders is a deadly disease lacking effective therapies. Targeted strategies which are currently in development are focusing on blocking individual receptors known to be involved in the myofibroblast transition. However, in light of recent evidence that Rho GTPase/myocardin‐related transcription factor (MRTF) regulated transcription is an essential and convergent downstream mechanism for myofibroblast transition; we explore the hypothesis that inhibitors of this pathway may represent novel antifibrotics. Consistent with previous findings, fibroblasts from SSc patients expressed markers of activated myofibroblasts but additionally, Rho/MRTF regulated genes were found to be elevated (4‐6 fold) in these samples. At low micromolar concentrations, a novel small‐molecule inhibitor of Rho/MRTF regulated transcription (CCG‐203971) blocked RNA and protein expression of multiple pro‐fibrotic markers including connective tissue growth factor (CTGF), alpha‐smooth muscle actin (α‐SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and transforming growth factor β (TGFβ)‐stimulated normal donor samples. In a mouse model for scleroderma, treatment with CCG‐203971 also prevented bleomycin‐induced skin thickening and collagen deposition. These data suggest targeting the Rho/MRTF gene transcription pathway could provide a novel approach to therapy for SSc and other fibrotic disorders.