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Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities

Nature Reviews Rheumatology volume 8, pages 42–54 (2012)Cite this article

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Abstract

Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.

Key Points

  • Fibrosis represents a deregulated and uncontrolled repair process that recapitulates features of embryonic development and normal wound healing

  • Fibrosis in systemic sclerosis (SSc) shares mechanisms that underlie organ-based fibrosing disorders such as idiopathic pulmonary fibrosis

  • Transforming growth factor β seems to be a master regulator of both physiological and pathological matrix remodeling, and might be responsible for maintaining the activated fibroblast phenotype in SSc

  • The Wnt–β-catenin, Hedgehog–Patched and Jagged–Notch pathways are important in embryological development, and seem to be aberrantly activated in some patients with SSc

  • Mesenchymal cells are chronically activated via self-amplifying loops, resulting in a vicious cycle of progressive fibrogenesis

  • Selective targeting of molecules and pathways involved in fibroblast activation, singly or in combination, offers new approaches to the treatment of fibrosis

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Figure 1: Cellular and molecular pathways underlying fibrosis in systemic sclerosis.
Figure 2: Tissue damage activates innate immune signaling, which transforms an orderly self-limited repair into a sustained, aberrant fibrogenic process.
Figure 3: Tissue fibrosis in SSc.

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Acknowledgements

This work was partially supported by grants from the National Institutes of Health (AR 42309) and the Scleroderma Research Foundation. We are grateful to Carol Feghali-Bostwick, Warren Tourtellotte, Monique Hinchcliff, Robert Lafyatis, Michael Whitfield, Cara Gottardi, Carol Artlett, Maria Trojanowska and members of the Northwestern Scleroderma Program for valuable discussions.

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  1. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, McGaw M300, 240 East Huron Street, Chicago, 60611, IL, USA

    Swati Bhattacharyya, Jun Wei & John Varga

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  1. Swati Bhattacharyya
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Bhattacharyya, S., Wei, J. & Varga, J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 8, 42–54 (2012). https://doi.org/10.1038/nrrheum.2011.149

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