Morphogen pathways as molecular targets for the treatment of fibrosis in systemic sclerosis

• Published in: Archives of Dermatological Research 2013, Vol.305 (1), p.1-8
• Main Authors: Beyer, Christian, Dees, Clara, Distler, Jörg H. W.
• Format: Article
• Language: English
• Subjects: Animals; Clinical trials; Collagen; Dermatology; Drug Design; Extracellular matrix; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; Homeostasis; Humans; Medicine; Medicine & Public Health; Molecular Targeted Therapy; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; Pathogenesis; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - metabolism; Regression analysis; Review Article; Scleroderma; Scleroderma, Systemic - diagnosis; Scleroderma, Systemic - drug therapy; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Signal transduction; Signal Transduction - drug effects; Systemic sclerosis; Wnt protein; Wnt Signaling Pathway - drug effects
• ISSN: 0340-3696; 1432-069X
• DOI: 10.1007/s00403-012-1304-7

Wnt-, Hedgehog- and Notch-signaling cascades are morphogen pathways that play crucial roles in development and tissue homeostasis. While morphogen pathways are tightly regulated at multiple levels, inappropriate activation of Wnt, Hedgehog and Notch signaling has been implicated into the pathogenesis of various diseases. In particular, Wnt, Hedgehog and Notch signaling have emerged as central players in the pathogenesis of fibrotic diseases. Here, we will review the pro-fibrotic effects of Wnt, Hedgehog and Notch signaling in systemic sclerosis (SSc), prototypical systemic fibrotic disease. Wnt, Hedgehog and Notch pathways are activated in SSc. They potently stimulate fibroblasts to differentiate into myofibroblasts and to release collagen and other extracellular matrix components. Genetic or pharmacological inhibition of morphogen pathways effectively prevents experimental fibrosis in different preclinical models and induces regression of pre-established fibrosis. As several inhibitors of Wnt, Hedgehog and Notch have recently been developed with first ones being already approved for clinical trials, morphogen pathways maybe a novel approach for the treatment of fibrosis.