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Figure 1.
Novel antifibrotic therapies in systemic sclerosis (SSc)
Excessive accumulation of extracellular matrix (ECM) causes severe tissue fibrosis in SSc. Antifibrotic therapies target profibrotic pathways in fibroblasts, the main producers of ECM. 1CAT-192 anti-transforming growth factor-b antibodies (TGF-ab) catch TGF-β molecules (TGF), which would bind to TGF-β receptors (TGFR) to activate potent profibrotic pathways. Smad molecules, including Smad 3, as well as the Abelson kinase (Abl) are downstream mediators of the profibrotic TGF-β pathway. 2Receptor tyrosine kinase inhibitors (RTKI) can block several profibrotic signaling cascades. Imatinib and nilotinib inhibit both Abl and the platelet-derived growth factor receptor (PDGFR). In addition to Abl and PDGFR, dasatinib blocks Src kinases (Src). 3The thiazolidinediones, a group of peroxisome proliferator-activated receptor-gamma agonists (PPARγA), bind to their intra-nuclear receptors to inhibit ECM production. 4Histone deacetylase inhibitors (HDACI) as well as 5DNA methyltransferase inhibitors (DNMTI) decrease ECM production by modifying gene transcription. |
