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Matrix Stiffness: the Conductor of Organ Fibrosis

  • Scleroderma (J Varga, Section Editor)
  • Published:
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Abstract

Purpose of Review

Organ fibrosis is a lethal component of scleroderma. The hallmark of scleroderma fibrosis is extensive extracellular matrix (ECM) deposition by activated myofibroblasts, specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. The purpose of this review is to discuss novel mechanistic insight into myofibroblast activation in scleroderma.

Recent Findings

Matrix stiffness, traditionally viewed as an end point of organ fibrosis, is now recognized as a critical regulator of tissue fibrogenesis that hijacks the normal physiologic wound-healing program to promote organ fibrosis. Here, we discuss how matrix stiffness orchestrates fibrosis by controlling three fundamental pro-fibrotic mechanisms: (a) mechanoactivation of myofibroblasts, (b) integrin-mediated latent transforming growth factor beta 1 (TGF-β1) activation, and (c) activation of non-canonical TGF-β1 signaling pathways. We also summarize novel therapeutic targets for anti-fibrotic therapy based on the mechanobiology of scleroderma.

Summary

Future research on mechanobiology of scleroderma may lead to important clinical applications such as improved diagnosis and treatment of patients with scleroderma and other fibrotic-related diseases.

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Acknowledgements

The authors would like to acknowledge Dr. Katy Black (Massachusetts General Hospital) for her careful review of the manuscript and helpful comments. D.L. gratefully acknowledge support from the Scleroderma Foundation, Scleroderma Research Foundation, American Thoracic Society Foundation and Pulmonary Fibrosis Foundation.

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Authors and Affiliations

  1. Fibrosis Research Center, Massachusetts General Hospital, Boston, MA, USA

    Alba Santos & David Lagares

  2. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA

    Alba Santos & David Lagares

  3. Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Alba Santos & David Lagares

  4. Harvard Medical School, Boston, MA, USA

    Alba Santos & David Lagares

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Santos, A., Lagares, D. Matrix Stiffness: the Conductor of Organ Fibrosis. Curr Rheumatol Rep 20, 2 (2018). https://doi.org/10.1007/s11926-018-0710-z

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