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  • Review Article
  • Published:

Fibrosis—a lethal component of systemic sclerosis

Nature Reviews Rheumatology volume 10, pages 390–402 (2014)Cite this article

Subjects

Key Points

  • Fibrosis is characterized by excessive accumulation of connective tissue components in organs or tissues, which is caused by deregulated wound-healing processes in response to chronic tissue injury and/or inflammation

  • Chronic tissue injury and inflammation—hallmarks of rheumatic diseases—are crucial in activating the tissue repair mechanisms that result in fibrosis in systemic sclerosis (SSc)

  • Fibrosis in SSc is typically characterized by prolonged and/or exaggerated activation of fibroblasts, a key feature of which is the differentiation of fibroblasts into myofibroblasts

  • Endoplasmic reticulum stress has been hypothesized to contribute to the initiation of fibrotic tissue remodelling in rheumatic diseases, and mechanical cues have a crucial role in determining fibroblast activation in fibrosis

  • Mechanotransduction, the capability of cells to transform mechanical cues into biochemical signals, has also been implicated in fibrotic mechanisms

  • Therapies targeting either persistent fibroblast activation (such as aberrant immune responses), or the chemical and mechanical stimuli that drive myofibroblast differentiation, could have the potential to alleviate the symptoms of SSc

Abstract

Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathological role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chemical and mechanical signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.

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Figure 1: Fibrogenesis in SSc.
Figure 2: ER stress and the development of fibrosis.
Figure 3: Targeting matrix stiffness and mechanotransduction in fibrosis.

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Acknowledgements

M.K. gratefully acknowledges support from the Canadian Institute of Health Research Operating Grants. D.L. and A.M.T. gratefully acknowledge support from NIH Heart Lung and Blood Institute–NIH grants R01-HL095732 and R01-HL108975, and from the Scleroderma Research Foundation.

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Authors and Affiliations

  1. Division of Surgical Research, Shriners Hospital for Children, McGill University, 1529 Cedar Avenue, Montreal, H3G1A6, QC, Canada

    Yuen Yee Ho

  2. Department of Medicine, Pulmonary and Critical Care Unit and Centre for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, 02129, MA, USA

    David Lagares & Andrew M. Tager

  3. Division of Orthopaedics, The Toronto Western Research Institute, Toronto Western Hospital, The University Health Network, 60 Leonard Avenue, Toronto, M5T 2S8, ON, Canada

    Mohit Kapoor

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All authors contributed equally to researching data for the article, providing a substantial contribution to discussions of the content, writing the article, and to the review and/or editing of the manuscript before submission.

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Correspondence to Mohit Kapoor.

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Ho, Y., Lagares, D., Tager, A. et al. Fibrosis—a lethal component of systemic sclerosis. Nat Rev Rheumatol 10, 390–402 (2014). https://doi.org/10.1038/nrrheum.2014.53

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