title: Novel insights into the function and dynamics of extracellular matrix in liver fibrosis.
abstract: Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases.
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark; University of Southern Denmark, SDU, Odense, Denmark; mk@nordicbioscience.com.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Tina
authors.initials: T
authors.lastname: Manon-Jensen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Federica
authors.initials: F
authors.lastname: Genovese
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Jacob H
authors.identifier: http://orcid.org/0000-0002-8467-0989
authors.initials: JH
authors.lastname: Kristensen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Mette J
authors.initials: MJ
authors.lastname: Nielsen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Jannie Marie B
authors.initials: JM
authors.lastname: Sand
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Niels-Ulrik B
authors.initials: NU
authors.lastname: Hansen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Bay-Jensen
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Cecilie L
authors.initials: CL
authors.lastname: Bager
authors.affiliation: Department of Gastroenterology and Hepatology, Odense University Hospital, University of Southern Denmark, Odense, Denmark;
authors.forename: Aleksander
authors.initials: A
authors.lastname: Krag
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom;
authors.forename: Andy
authors.initials: A
authors.lastname: Blanchard
authors.affiliation: Section of Molecular Biology, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark;
authors.forename: Henrik
authors.initials: H
authors.lastname: Krarup
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark;
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Leeming
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000473:pathology* / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008954:Models, Biological
chemical_list: D016326:Extracellular Matrix Proteins
keywords: collagen; cytokine; endocrine; extracellular fibrogenesis; integrin; laminin; matrix metalloproteinase; posttranslational modification; proteoglycan