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

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

39 Citationer (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 upregulation 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 wildtype mice by chronic CCl(4) administration. A strong upregulation of uPARAP/Endo180 was observed in wildtype 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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
OriginalsprogEngelsk
TidsskriftJournal of Pathology
Vol/bind227
Udgave nummer1
Sider (fra-til)94-105
ISSN0022-3417
DOI
StatusUdgivet - maj 2012

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