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Systemic sclerosis: a prototypic multisystem fibrotic disorder
John Varga, David Abraham
John Varga, David Abraham
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):557-567. https://doi.org/10.1172/JCI31139.
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Review Series

Systemic sclerosis: a prototypic multisystem fibrotic disorder

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Abstract

A unique feature of systemic sclerosis (SSc) that distinguishes it from other fibrotic disorders is that autoimmunity and vasculopathy characteristically precede fibrosis. Moreover, fibrosis in SSc is not restricted to a single organ, but rather affects many organs and accounts for much of the morbidity and mortality associated with this disease. Although immunomodulatory drugs have been used extensively in the treatment of SSc, no therapy to date has been able to reverse or slow the progression of tissue fibrosis or substantially modify the natural progression of the disease. In this Review, we highlight recent studies that shed light on the cellular and molecular mechanisms underlying the fibrotic process in SSc and that identify cellular processes and intra- and extracellular proteins as potential novel targets for therapy in this prototypic multisystemic fibrotic disease.

Authors

John Varga, David Abraham

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Figure 4

TGF-β signaling through non-SMAD pathways.

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TGF-β signaling through non-SMAD pathways.
Receptor activation by TGF-β ...
Receptor activation by TGF-β can cause activation of non-SMAD pathways involved in regulating cell proliferation, cytoskeletal rearrangement, ECM synthesis, and apoptosis. Activation of intracellular protein and lipid kinase cascades results in activation of DNA-binding transcription factors and regulation of gene expression. These signal transdution pathways might converge on or interact with the canonical SMAD pathway or operate completely independent of SMAD pathways. AP-1, acivator protein 1; EGR-1, early growth response 1; PAK2, p21-activated kinase 2; ROCK, Rho-associated, coiled-coil containing protein kinase 1; TAB1/2, TAK1-binding protein 1/2; TAK1, TGF-β activated kinase 1.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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