Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr;9(8):728.
doi: 10.21037/atm-20-2948.

It's all about the spaces between cells: role of extracellular matrix in liver fibrosis

Amit Khurana  1   2 , Nilofer Sayed  3 , Prince Allawadhi  4 , Ralf Weiskirchen  2
Affiliations
Review

It's all about the spaces between cells: role of extracellular matrix in liver fibrosis

Amit Khurana et al. Ann Transl Med. 2021 Apr.

Abstract

Liver fibrosis is one of the leading complications of a variety of chronic liver disorders, including the nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver cirrhosis and liver failure. The progression of liver fibrosis is driven by chronic inflammation, which activates the secretory fibroblasts to the myofibroblast phenotype. These specialized liver cells are called as hepatic stellate cells (HSCs). The excessive extracellular matrix (ECM) secretion creates a large number of complications. Fibrosis is the result of imbalance between the matrix synthesizing and matrix degrading factors. The major ECM proteins include the matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), lysyl oxidases (LOX), lysyl oxidase-like (LOXLs) enzymes, tenascins and others. These ECM proteins present novel avenues for the therapeutics of liver fibrosis. The current review highlights the major role played by these critical matrix proteins in liver fibrosis. Further, some of the targeted formulations used against these proteins are discussed and suggestions are provided to select the course of research for successful clinical translation of basic research findings for the amelioration of liver fibrosis.

Keywords: Liver fibrosis; extracellular matrix; lysyl oxidases (LOX); matrix metalloproteinases (MMPs); tissue inhibitor of metalloproteinases (TIMPs).

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2948). The series “Unresolved Basic Issues in Hepatology” was commissioned by the editorial office without any funding or sponsorship. RW served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Translational Medicine from Aug 2020 to Jul 2022. The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The role of various extracellular matrix proteins in the pathogenesis of liver fibrosis. Individual activities of proteoglycans and enzymes are depicted. Under physiological conditions, the concert of these proteins guarantees a balanced synthesis of extracellular matrix (ECM). However, under pathogenetic conditions, it comes to overshooting reactions resulting in dysregulation in deposition and degradation of ECM, finally resulting in fibrosis. LO, lysyl oxidase(s); LOXL2, lysyl oxidase homolog 2.
Figure 2
Figure 2
The role of tenascins in the pathogenesis of liver fibrosis. Tenascins significantly contribute to liver fibrosis by stimulating profibrogenic signaling and modulating functions of the extracellular matrix (ECM). MMPs, matrix metalloproteinases; SMAD, small mothers against decapentaplegic comprising a family of structurally similar proteins acting as main signal transducers for receptors of the TGF-β superfamily; TGF-β, transforming growth factor-β.
See this image and copyright information in PMC

References

    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-18. 10.1172/JCI24282 - DOI - PMC - PubMed
    1. Friedman SL. Liver fibrosis–from bench to bedside. J Hepatol 2003;38:S38-53. 10.1016/S0168-8278(02)00429-4 - DOI - PubMed
    1. Sarin SK, Maiwall R. Global burden of liver disease: a true burden on health sciences and economies. World Gastroenterol Organisation 2012;17:35-40.
    1. Cotoi CG, Quaglia A. Normal Liver Anatomy and Introduction to Liver Histology. In: Textbook of Pediatric Gastroenterology, Hepatology and Nutrition. Springer, 2016:609-12.
    1. Biagini G, Ballardini G. Liver fibrosis and extracellular matrix. J Hepatol 1989;8:115-24. 10.1016/0168-8278(89)90170-0 - DOI - PubMed

LinkOut - more resources