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.
authors.affiliation: The Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Madsen
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Jürgensen
authors.forename: Signe
authors.initials: S
authors.lastname: Ingvarsen
authors.forename: Maria C
authors.initials: MC
authors.lastname: Melander
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.forename: Andreas
authors.initials: A
authors.lastname: Hald
authors.forename: Birgitte
authors.initials: B
authors.lastname: Rønø
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Madsen
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.forename: Lars H
authors.initials: LH
authors.lastname: Engelholm
authors.forename: Niels
authors.initials: N
authors.lastname: Behrendt
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D008562:Membrane Glycoproteins; C474081:Mrc2 protein, mouse; D011956:Receptors, Cell Surface; D003094:Collagen