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Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy
Journal article   Open access   Peer reviewed

Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy

Jun Wei, Swati Bhattacharyya, Warren G Tourtellotte, John Varga and Carol Artlett
Autoimmunity reviews, v 10(5), pp 267-275
01 Mar 2011
DOI: https://doi.org/10.1016/j.autrev.2010.09.015
PMID: 20863909
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc3998379View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Adipocytes - metabolism Adipocytes - pathology Animals beta Catenin - metabolism Biomarkers - analysis Cell Transdifferentiation Epithelial Cells - metabolism Epithelial Cells - pathology Fibrillin-1 Fibrillins Fibroblasts - metabolism Fibroblasts - pathology Fibrosis - metabolism Fibrosis - pathology Fibrosis - therapy Humans Hypoxia - metabolism Hypoxia - pathology Mice Microfilament Proteins - metabolism Molecular Targeted Therapy - methods Pericytes - metabolism Pericytes - pathology PPAR gamma - metabolism Scleroderma, Systemic - metabolism Scleroderma, Systemic - pathology Scleroderma, Systemic - therapy Toll-Like Receptors - metabolism Transforming Growth Factor beta - metabolism Wnt Proteins - metabolism Signal Transduction
Systemic sclerosis (SSc) is a complex and incompletely understood disease associated with fibrosis in multiple organs. Recent findings identify transforming growth factor-ß (TGF-ß), Wnt ligands, toll-like receptor-mediated signaling, hypoxia, type I interferon, type 2 immune responses and mechanical stress as extracellular cues that modulate fibroblast function and differentiation, and as potential targets for therapy. Moreover, fibrillin-1 has a major role in storing and regulating the bioavailability of TGF-ß and other cytokines, and fibrillin-1 mutations are implicated in a congenital form of scleroderma called stiff skin syndrome. Fibrosis is due not only to the activation of tissue-resident fibroblasts and their transdifferentiation into myofibroblasts, but also the differentiation of bone marrow-derived fibrocytes, and transition of endothelial and epithelial cells, pericytes and adipocytes into activated mesenchymal cells. These responses are modulated by signaling mediators and microRNAs that amplify or inhibit TGF-ß and Wnt signaling. Gain-of-function and loss-of-function abnormalities of these mediators may account for the characteristic activated phenotype of SSc fibroblasts. The nuclear orphan receptor PPAR-γ plays a particularly important role in limiting the duration and intensity of fibroblast activation and differentiation, and impaired PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways, mediators and differentiation programs that are responsible for SSc tissue damage allows their selective targeting. This in turn opens the door for therapies utilizing novel compounds, or drug repurposing by innovative uses of already-approved drugs. In view of the heterogeneous clinical presentation and unpredictable course of SSc, as well as its complex pathogenesis, only robust clinical trials incorporating the judicious application of biomarkers will be able to clarify the clinical utility of these innovative approaches.

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Web of Science research areas
Immunology
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