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.).
J Pharmacol Exp Ther. 2014 Jun;349(3):480-6. doi: 10.1124/jpet.114.213520. Epub 2014 Apr 4.
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.
系统性硬化症（SSc），又称硬皮病，与许多纤维化疾病相似，缺乏有效的治疗方法。目前的临床试验集中在抗炎药物或靶向治疗上，旨在针对纤维化起始的众多受体机制之一。鉴于证据表明，Rho GTPases 诱导的肌球蛋白相关转录因子（MRTF）和血清反应因子（SRF）调节的基因转录程序对于肌成纤维细胞的激活至关重要，我们探讨了这样一种假设，即该途径的抑制剂可能代表新型抗纤维化药物。MRTF/SRF 调节的基因在弥漫性皮肤型 SSc 患者的原代真皮成纤维细胞中自发表达增加。一种新型的 MRTF/SRF 调节转录的小分子抑制剂（CCG-203971）可抑制 SSc 成纤维细胞和溶血磷脂酸（LPA）和转化生长因子β（TGFβ）刺激的成纤维细胞中结缔组织生长因子（CTGF）、α-平滑肌肌动蛋白（α-SMA）和胶原 1（COL1A2）的表达。CCG-203971 的体内治疗还可预防博来霉素诱导的皮肤增厚和胶原沉积。因此，靶向 MRTF/SRF 基因转录途径可能为 SSc 和其他纤维化疾病的治疗提供一种有效的新方法。
