title: Collagen XVIII in tissue homeostasis and dysregulation - Lessons learned from model organisms and human patients.
abstract: Collagen XVIII is a ubiquitous basement membrane (BM) proteoglycan produced in three tissue-specific isoforms that differ in their N-terminal non-collagenous sequences, but share collagenous and C-terminal non-collagenous domains. The collagenous domain provides flexibility to the large collagen XVIII molecules on account of multiple interruptions in collagenous sequences. Each isoform has a complex multi-domain structure that endows it with an ability to perform various biological functions. The long isoform contains a frizzled-like (Fz) domain with Wnt-inhibiting activity and a unique domain of unknown function (DUF959), which is also present in the medium isoform. All three isoforms share an N-terminal laminin-G-like/thrombospondin-1 sequence whose specific functions still remain unconfirmed. The proteoglycan nature of the isoforms further increases the functional diversity of collagen XVIII. An anti-angiogenic domain termed endostatin resides in the C-terminus of collagen XVIII and is proteolytically cleaved from the parental molecule during the BM breakdown for example in the process of tumour progression. Recombinant endostatin can efficiently reduce tumour angiogenesis and growth in experimental models by inhibiting endothelial cell migration and proliferation or by inducing their death, but its efficacy against human cancers is still a subject of debate. Mutations in the COL18A1 gene result in Knobloch syndrome, a genetic disorder characterised mainly by severe eye defects and encephalocele and, occasionally, other symptoms. Studies with gene-modified mice have elucidated some aspects of this rare disease, highlighting in particular the importance of collagen XVIII in the development of the eye. Research with model organisms have also helped in determining other structural and biological functions of collagen XVIII, such as its requirement in the maintenance of BM integrity and its emerging roles in regulating cell survival, stem or progenitor cell maintenance and differentiation and inflammation. In this review, we summarise current knowledge on the properties and endogenous functions of collagen XVIII in normal situations and tissue dysregulation. When data is available, we discuss the functions of the distinct isoforms and their specific domains.
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland; Centre for Cancer Biomarkers CCBIO, Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway. Electronic address: ritva.heljasvaara@oulu.fi.
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Ruotsalainen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024102:Collagen Type VIII / Q000235:genetics* / Q000378:metabolism; D043170:Collagen Type XVIII; D004677:Encephalocele / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D043169:Endostatins / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000072417:Protein Domains; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011994:Recombinant Proteins / Q000494:pharmacology; D012162:Retinal Degeneration; D012163:Retinal Detachment / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C000612902:COL18A1 protein, human; D024102:Collagen Type VIII; D043170:Collagen Type XVIII; D043169:Endostatins; D020033:Protein Isoforms; D011994:Recombinant Proteins
keywords: Basement membrane; Heparan sulphate proteoglycan; Knobloch syndrome; Multiplexin