Elsevier

Advanced Drug Delivery Reviews

Volume 97, 1 February 2016, Pages 4-27
Advanced Drug Delivery Reviews

Extracellular matrix structure

https://doi.org/10.1016/j.addr.2015.11.001Get rights and content

Abstract

Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions. This article emphasizes in the complex ECM structure as to provide a better understanding of its dynamic structural and functional multipotency. Where relevant, the implication of the various families of ECM macromolecules in health and disease is also presented.

Section snippets

Types of extracellular matrices: structure and properties

All tissues and organs contain a mixture of cells and non-cellular components, which form well-organized networks called extracellular matrices (ECMs). The ECMs provide not only physical scaffolds into which cells are embedded but also regulate many cellular processes including growth, migration, differentiation, survival, homeostasis, and morphogenesis [1], [2], [3]. The ECMs consist of a large variety of matrix macromolecules whose precise composition and specific structures vary from tissue

Proteoglycans and hyaluronan

PGs are among the most important structural and functional biomacromolecules in tissues. They consist of a core protein onto which one or more GAG chains of the same or different type are covalently attached. GAGs are long highly negatively charged heteropolysaccharides that contain repeating disaccharides composed mainly of N-acetylated hexosamines (N-acetyl-D-galactosamine or N-acetyl-D-glucosamine) and D-/L-hexuronic acid (D-glucuronic acid or L-iduronic acid). There are six types of

Extracellular matrix proteases

Our view of proteases has come a long way since they were first introduced as generic destructive enzymes associated with protein catabolism and generation of peptides and amino acids during the early stages of protein evolution. The understanding that proteases constitute more than 2% of the total genes in the human genome highlights their contribution in physiological cellular functions as sharp selective scissors, regulating fate, localization, and activity of a variety of proteins,

Extracellular matrix receptors

Apart from the cell surface PGs syndecans and glypicans described above, other ECM receptors include two major receptor families named integrins and DDRs, as well as the HA receptor CD44.

Extracellular matrix targeting: Novel therapeutic approaches

ECM is markedly modified in all pathologies, such as atherosclerosis, autoimmune and inflammatory diseases, and cancer. Nowadays, the microenvironment, in which diseases progress, is thought as equally important as cell populations implicated in the development of the pathologic conditions. For example, healthy microenvironment prevents the cancerous outgrowth of epithelial cells, whereas perturbation of homeostasis enables the initiation and progression of malignancy as well as the emergence

Conclusion

ECM is a complex and dynamic structure that provides the scaffold wherein cells are located. Matrix components encompass multiple, independently folded domains as well as specific glycosylation that provide them with specific sites for interaction. ECM components, such as collagens, PGs, GAGs, elastin, laminin, FN, and matricellular proteins contain various interacting sites with different specificities to matrix components and cell surface receptors, which make them capable to bind with each

Acknowledgments

This research has been co-financed by the European Union (European Social Fund—ESF) and Greek National Funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) Research Funding Program: Thales. Investing in knowledge society through the European Social Fund.

References (377)

  • N. Itano et al.

    Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties

    J. Biol. Chem.

    (1999)
  • T.N. Wight et al.

    Versican and the control of inflammation

    Matrix Biol.

    (2014)
  • T.N. Wight et al.

    Versican and the regulation of cell phenotype in disease

    Biochim. Biophys. Acta

    (2014)
  • S.P. Reese et al.

    Effects of decorin proteoglycan on fibrillogenesis, ultrastructure, and mechanics of type I collagen gels

    Matrix Biol.

    (2013)
  • A.A. Dunkman et al.

    Decorin expression is important for age-related changes in tendon structure and mechanical properties

    Matrix Biol.

    (2013)
  • S. Chen et al.

    Interclass small leucine-rich repeat proteoglycan interactions regulate collagen fibrillogenesis and corneal stromal assembly

    Matrix Biol.

    (2014)
  • R.V. Iozzo et al.

    Decorin is a biological ligand for the epidermal growth factor receptor

    J. Biol. Chem.

    (1999)
  • A. Morcavallo et al.

    Decorin differentially modulates the activity of insulin receptor isoform A ligands

    Matrix Biol.

    (2014)
  • Z. Horvath et al.

    Decorin deficiency promotes hepatic carcinogenesis

    Matrix Biol.

    (2014)
  • L. Schaefer et al.

    Small leucine-rich proteoglycans, at the crossroad of cancer growth and inflammation

    Curr. Opin. Genet. Dev.

    (2012)
  • S.S. Skandalis et al.

    Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans

    Matrix Biol.

    (2014)
  • K. Nikolovska et al.

    A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function

    Matrix Biol.

    (2014)
  • S. Vesentini et al.

    Estimation of the binding force of the collagen molecule-decorin core protein complex in collagen fibril

    J. Biomech.

    (2005)
  • A. De Luca et al.

    Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases

    J. Biol. Chem.

    (1996)
  • J.X. Zhu et al.

    Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis

    J. Biol. Chem.

    (2005)
  • G. Csordas et al.

    Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo

    J. Biol. Chem.

    (2000)
  • S. Buraschi et al.

    Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels

    J. Biol. Chem.

    (2010)
  • T. Neill et al.

    Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1alpha, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3

    J. Biol. Chem.

    (2012)
  • H. Jarvelainen et al.

    Pivotal role for decorin in angiogenesis

    Matrix Biol.

    (2015)
  • T. Neill et al.

    Instructive roles of extracellular matrix on autophagy

    Am. J. Pathol.

    (2014)
  • A.D. Berendsen et al.

    Biglycan modulates angiogenesis and bone formation during fracture healing

    Matrix Biol.

    (2014)
  • A. Babelova et al.

    Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors

    J. Biol. Chem.

    (2009)
  • A. Sjoberg et al.

    The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q

    J. Biol. Chem.

    (2005)
  • J. Jian et al.

    Fibromodulin promoted in vitro and in vivo angiogenesis

    Biochem. Biophys. Res. Commun.

    (2013)
  • M.F. D'Onofrio et al.

    Identification of beta1 integrin as mediator of melanoma cell adhesion to lumican

    Biochem. Biophys. Res. Commun.

    (2008)
  • S. Brezillon et al.

    Lumican core protein inhibits melanoma cell migration via alterations of focal adhesion complexes

    Cancer Lett.

    (2009)
  • D. Nikitovic et al.

    Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response

    Matrix Biol.

    (2014)
  • D. Nikitovic et al.

    Lumican regulates osteosarcoma cell adhesion by modulating TGFbeta2 activity

    Int. J. Biochem. Cell Biol.

    (2011)
  • K. Pietraszek et al.

    Lumican: a new inhibitor of matrix metalloproteinase-14 activity

    FEBS Lett.

    (2014)
  • M. Mongiat et al.

    Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan

    J. Biol. Chem.

    (2003)
  • C. Poluzzi et al.

    Endorepellin evokes autophagy in endothelial cells

    J. Biol. Chem.

    (2014)
  • S.P. Smirnov et al.

    Conjugation of LG domains of agrins and perlecan to polymerizing laminin-2 promotes acetylcholine receptor clustering

    J. Biol. Chem.

    (2005)
  • C. Huze et al.

    Identification of an agrin mutation that causes congenital myasthenia and affects synapse function

    Am. J. Hum. Genet.

    (2009)
  • C. Frantz et al.

    The extracellular matrix at a glance

    J. Cell Sci.

    (2010)
  • A.D. Theocharis et al.

    Extracellular matrix: a functional scaffold

  • V.S. LeBleu et al.

    Structure and function of basement membranes

    Exp. Biol. Med.

    (2007)
  • W. Halfter et al.

    New concepts in basement membrane biology

    FEBS J.

    (2015)
  • M. Paulsson

    Basement membrane proteins: structure, assembly, and cellular interactions

    Crit. Rev. Biochem. Mol. Biol.

    (1992)
  • C.A. Kirkpatrick et al.

    Heparan sulfate proteoglycans at a glance

    J. Cell Sci.

    (2007)
  • H. Jarvelainen et al.

    Extracellular matrix molecules: potential targets in pharmacotherapy

    Pharmacol. Rev.

    (2009)
  • Cited by (0)

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Extracellular Matrix (ECM) and ECM-like materials: Therapeutic Tools and Targets in Cancer Treatment”.

    View full text