Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Endocytic collagen degradation : a novel mechanism involved in protection against liver fibrosis. / Madsen, Daniel H.; Jürgensen, Henrik J.; Ingvarsen, Signe Ziir; Melander, Maria C.; Vainer, Ben; Egerod, Kristoffer Lihme; Hald, Andreas; Rønø, Birgitte; Madsen, Charlotte A.; Bugge, Thomas H.; Engelholm, Lars H.; Behrendt, Niels.
In: Journal of Pathology, Vol. 227, No. 1, 2012, p. 94-105.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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
N1 - Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2012
Y1 - 2012
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
VL - 227
SP - 94
EP - 105
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 1
ER -
ID: 38287370