Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis

Daniel H. Madsen; Henrik J. Jürgensen; Signe Ziir Ingvarsen; Maria C. Melander; Ben Vainer; Kristoffer Lihme Egerod; Andreas Hald; Birgitte Rønø; Charlotte A. Madsen; Thomas H. Bugge; Lars H. Engelholm; Niels Behrendt

doi:10.1002/path.3981

Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis

Daniel H. Madsen, Henrik J. Jürgensen, Signe Ziir Ingvarsen, Maria C. Melander, Ben Vainer, Kristoffer Lihme Egerod, Andreas Hald, Birgitte Rønø, Charlotte A. Madsen, Thomas H. Bugge, Lars H. Engelholm, Niels Behrendt

32 Citations (Scopus)

Abstract

Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.

Original language	English
Journal	Journal of Pathology
Volume	227
Issue number	1
Pages (from-to)	94-105
Number of pages	12
ISSN	0022-3417
DOIs	https://doi.org/10.1002/path.3981
Publication status	Published - May 2012

Keywords

Animals
Antibodies, Blocking
Cell Line
Collagen
Endocytosis
Female
Fibroblasts
Hepatic Stellate Cells
Humans
Liver Cirrhosis, Experimental
Membrane Glycoproteins
Mice
Mice, Inbred Strains
Mice, Knockout
Receptors, Cell Surface
Up-Regulation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/path.3981

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@article{37304c8352624f01af09e781a83d9a36,

title = "Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis",

abstract = "Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.",

keywords = "Animals, Antibodies, Blocking, Cell Line, Collagen, Endocytosis, Female, Fibroblasts, Hepatic Stellate Cells, Humans, Liver Cirrhosis, Experimental, Membrane Glycoproteins, Mice, Mice, Inbred Strains, Mice, Knockout, Receptors, Cell Surface, Up-Regulation",

author = "Madsen, {Daniel H.} and J{\"u}rgensen, {Henrik J.} and Ingvarsen, {Signe Ziir} and Melander, {Maria C.} and Ben Vainer and Egerod, {Kristoffer Lihme} and Andreas Hald and Birgitte R{\o}n{\o} and Madsen, {Charlotte A.} and Bugge, {Thomas H.} and Engelholm, {Lars H.} and Niels Behrendt",

note = "Copyright {\textcopyright} 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2012",

month = may,

doi = "10.1002/path.3981",

language = "English",

volume = "227",

pages = "94--105",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "JohnWiley & Sons Ltd",

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TY - JOUR

T1 - Endocytic collagen degradation

T2 - a novel mechanism involved in protection against liver fibrosis

AU - Madsen, Daniel H.

AU - Jürgensen, Henrik J.

AU - Ingvarsen, Signe Ziir

AU - Melander, Maria C.

AU - Vainer, Ben

AU - Egerod, Kristoffer Lihme

AU - Hald, Andreas

AU - Rønø, Birgitte

AU - Madsen, Charlotte A.

AU - Bugge, Thomas H.

AU - Engelholm, Lars H.

AU - Behrendt, Niels

PY - 2012/5

Y1 - 2012/5

N2 - Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.

AB - Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.

KW - Animals

KW - Antibodies, Blocking

KW - Cell Line

KW - Collagen

KW - Endocytosis

KW - Female

KW - Fibroblasts

KW - Hepatic Stellate Cells

KW - Humans

KW - Liver Cirrhosis, Experimental

KW - Membrane Glycoproteins

KW - Mice

KW - Mice, Inbred Strains

KW - Mice, Knockout

KW - Receptors, Cell Surface

KW - Up-Regulation

U2 - 10.1002/path.3981

DO - 10.1002/path.3981

M3 - Journal article

C2 - 22294280

SN - 0022-3417

VL - 227

SP - 94

EP - 105

JO - Journal of Pathology

JF - Journal of Pathology

IS - 1

ER -

Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis

Abstract

Keywords

UN SDGs

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