肌钙蛋白
血清反应因子
CTGF公司
肌成纤维细胞
转录因子
纤维化
癌症研究
生物
转化生长因子
生长因子
结缔组织
细胞生物学
医学
病理
基因
受体
遗传学
作者
Andrew J. Haak,Pei‐Suen Tsou,M. Asif Amin,Jeffrey H. Ruth,Phillip L. Campbell,David A. Fox,Dinesh Khanna,Scott D. Larsen,Richard R. Neubig
标识
DOI:10.1124/jpet.114.213520
摘要
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.
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