Back to the future: targeting the extracellular matrix to treat systemic sclerosis

ABSTRACT Fibrosis is the excessive deposition of a stable extracellular matrix (ECM); fibrotic tissue is composed principally of highly crosslinked type I collagen and highly contractile

myofibroblasts. Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by skin and organ fibrosis. The fibrotic process has been recognized in SSc for

>40 years, but drugs with demonstrable efficacy against SSc fibrosis in ameliorating the lung involvement have only recently been identified. Unfortunately, these treatments are

ineffective at improving the skin score in patients with SSc. Previous clinical trials in SSc have largely focused on the cross-purposing of anti-inflammatory drugs and the use of

immunosuppressive drugs from the transplantation field, which address inflammatory and/or autoimmune processes. Limited examination has taken place of specific anti-fibrotic agents developed

through their ability to directly target the ECM in SSc by, for example, alleviating the persistent matrix stiffness and mechanotransduction that might be required for both the initiation

and maintenance of fibrosis, including in SSc. However, because of the importance of the ECM in the SSc phenotype, attempts have now been made to identify drugs that specifically target the

ECM, including some drugs that are currently under consideration for the treatment of cancer. KEY POINTS * Systemic sclerosis (SSc) is a fibrotic disease, and anti-fibrotic agents deserve

consideration as treatments for this disease. * Major efforts have been made in the past ~20–25 years to uncover common mechanisms underlying fibrotic disease, including mechanotransductive

pathways and enzymes that directly affect extracellular matrix stiffness. * Potential SSc targets include collagen prolyl 4-hydroxylase, lysyl oxidase, focal adhesion kinase, TGFβ-activating

integrin subunits, TGFβ-activated kinase 1, yes-associated protein 1, myocardin-related transcription factor A and cellular communication network factors. * Current efforts are focused on

understanding how fibroblast subsets respond excessively to inflammation in fibrosis. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * College of Dentistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Andrew Leask & Angha Naik * Centre for

Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London, UK Richard J. Stratton Authors * Andrew Leask View author publications You can also search for this author

inPubMed Google Scholar * Angha Naik View author publications You can also search for this author inPubMed Google Scholar * Richard J. Stratton View author publications You can also search

for this author inPubMed Google Scholar CONTRIBUTIONS All authors researched data for the article. A.L. and R.J.S. contributed substantially to discussion of the content. All authors wrote

the article. All authors reviewed and/or edited the manuscript before submission. CORRESPONDING AUTHOR Correspondence to Andrew Leask. ETHICS DECLARATIONS COMPETING INTERESTS The authors

declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Reviews Rheumatology_ thanks Yoshihide Asano, Gabriela Kania and the other, anonymous, reviewer(s) for their

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Leask, A., Naik, A. & Stratton, R.J. Back to the future: targeting the extracellular matrix to treat systemic sclerosis. _Nat Rev

Rheumatol_ 19, 713–723 (2023). https://doi.org/10.1038/s41584-023-01032-1 Download citation * Accepted: 31 August 2023 * Published: 03 October 2023 * Issue Date: November 2023 * DOI:

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