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Type VI Collagen: Biological Functions and Its Neo-epitope as Hepatic Fibrosis Biomarker

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Biomarkers in Liver Disease

Abstract

Collagen VI forms a filamentous network in connective tissue, linking matrix macromolecules and cells. It is composed of three genetically distinct chains, α1(VI), α2(VI), and α3(VI), with a globular domain at each end. Additionally, three novel chains α4, α5, and α6 have been identified. Intracellularly, collagen VI monomers dimerize and form tetramers, which are secreted and then associate into filaments extracellularly. Gene expression for collagen VI is regulated differently than collagen I or III. Collagen VI interacts with collagen V and fibronectin, contributing to the structural integrity of tissue scaffolds. Moreover, it mediates cell adhesion and promotes migration. Soluble collagen VI acts as a sensor for tissue damage, modulating mesenchymal cell proliferation and survival, matrix homeostasis, and wound healing. Collagen VI-deficient mouse models have been generated, which have been used to investigate collagen VI-related myopathies, mammary carcinogenesis, and skeletal muscle satellite cell homeostasis. Collagen VI expression is upregulated in fibrosis of the adipose tissue and liver. Elevated collagen VI in the circulation is considered an indicator of early alcoholic liver fibrosis. Hepatic stellate cells (HSCs) are likely the source of perisinusoidal collagen VI. Collagen VI immunostaining is enhanced in fibrotic foci, codistributing with collagens I, III, and V. The α2(VI) chain sequesters hepatic matrix metalloproteinase (MMP)-1, MMP-3, and MMP-8 and blocks enzyme activation, preventing fibrolysis. The collagen VI receptor on HSCs offers selective targets for antifibrotic agents. CO6-MMP, a collagen VI neo-epitope generated by the proteolytic actions of MMP-2 and MMP-9, serves as a noninvasive biomarker in experimental liver fibrogenesis.

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Abbreviations

BM:

Bethlem myopathy

CCl4 :

Carbon tetrachloride

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

HSA:

Human serum albumin

HSC:

Hepatic stellate cell

MMP:

Matrix metalloproteinase

MMTV-PyMT:

Mammary tumor virus-polyoma middle T antigen

TGF-β:

Transforming growth factor-β

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Authors and Affiliations

  1. Department of Medical Education/Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Ki M. Mak

  2. Department of Medical Education, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Chien Yi M. Png

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  1. Ki M. Mak
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Correspondence to Ki M. Mak or Chien Yi M. Png .

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  1. Sciences Division, King's College, London, United Kingdom

    Victor R. Preedy

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Mak, K.M., Png, C.Y. (2015). Type VI Collagen: Biological Functions and Its Neo-epitope as Hepatic Fibrosis Biomarker. In: Preedy, V. (eds) Biomarkers in Liver Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7742-2_6-1

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