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The Structure and Function of Normal and Mutated Collagen Ix

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The Structure and Function of Normal and Mutated Collagen Ix D956etukansi.kesken.fm Page 1 Monday, November 5, 2007 12:17 PM D 956 OULU 2007 D 956 UNIVERSITY OF OULU P.O. Box 7500 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA D SERIES EDITORS Juha Jäälinoja MEDICA JuhaJäälinoja ASCIENTIAE RERUM NATURALIUM Professor Mikko Siponen THE STRUCTURE AND BHUMANIORA FUNCTION OF NORMAL AND Professor Harri Mantila MUTATED COLLAGEN IX CTECHNICA Professor Juha Kostamovaara DMEDICA Professor Olli Vuolteenaho ESCIENTIAE RERUM SOCIALIUM Senior Assistant Timo Latomaa FSCRIPTA ACADEMICA Communications Officer Elna Stjerna GOECONOMICA Senior Lecturer Seppo Eriksson EDITOR IN CHIEF Professor Olli Vuolteenaho EDITORIAL SECRETARY Publications Editor Kirsti Nurkkala FACULTY OF MEDICINE, DEPARTMENT OF MEDICAL BIOCHEMISTRY AND MOLECULAR BIOLOGY, BIOCENTER OULU, ISBN 978-951-42-8653-7 (Paperback) UNIVERSITY OF OULU ISBN 978-951-42-8654-4 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) ACTA UNIVERSITATIS OULUENSIS D Medica 956 JUHA JÄÄLINOJA THE STRUCTURE AND FUNCTION OF NORMAL AND MUTATED COLLAGEN IX Academic dissertation to be presented, with the assent of the Faculty of Medicine of the University of Oulu, for public defence in Auditorium F101 of the Department of Physiology (Aapistie 7), on December 21st, 2007, at 1 p.m. OULUN YLIOPISTO, OULU 2007 Copyright © 2007 Acta Univ. Oul. D 956, 2007 Supervised by Professor Leena Ala-Kokko Reviewed by Professor Yrjö Konttinen Docent Asta Pirskanen ISBN 978-951-42-8653-7 (Paperback) ISBN 978-951-42-8654-4 (PDF) http://herkules.oulu.fi/isbn9789514286544/ ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) http://herkules.oulu.fi/issn03553221/ Cover design Raimo Ahonen OULU UNIVERSITY PRESS OULU 2007 Jäälinoja, Juha, The structure and function of normal and mutated collagen IX Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Biocenter Oulu, University of Oulu, P.O. Box 5000, FI-90014 University of Oulu, Finland Acta Univ. Oul. D 956, 2007 Oulu, Finland Abstract Collagen IX belongs to the superfamily of collagenous proteins and is present on the surface of the heterotypic collagen fibrils that are predominantly composed of collagen II, and also collagen XI. The major sites of expression of collagen IX include the articular cartilage, intervertebral disc, inner ear and the vitreous body of the eye. Previous reports have indicated that mutations in the genes encoding the three polypeptide chains of collagen IX may lead to intervertebral disc disease and multiple epiphyseal dysplasia, a chondrodysplasia characterized by early onset osteoarthritis. These observations and results from genetically modified mouse lines suggest that collagen IX is crucial in the maintenance of the long- term integrity of tissues. However, the structure-function relationship as well as detailed information concerning the functional roles of this protein has remained unclear. Recombinant human collagen IX was obtained using an insect cell expression system. Besides full-length molecules, five truncated variants of collagen IX were produced to examine chain association and trimerization. Contrary to previous observations, it was shown that the COL1 and NC1 domains are not essential for trimerization. Instead, they seem to play an important role in the specificity of chain selection. The results also suggest that the N-terminal domains, NC3 or COL3, are required for complete folding and stabilization of collagen IX molecules, implicating cooperativity between different domains in the folding process. Collagen IX was found to mediate cell adhesion and bind efficiently to collagen receptor integrins α1β1, α2β1, α10β1 and α11β1. The binding was found to represent a novel type of mechanism, and the binding site of the integrin I domain was located at the N-terminal end of the COL3 domain in collagen IX. The obtained results suggest that the FACITs may play an important role as mediators of cell adhesion to collagen fibrils. Antibodies binding to human recombinant collagen IX were measured among 53 patients with seropositive rheumatoid arthritis (RA). These autoantibodies were significantly elevated among the RA patients when compared to the controls, suggesting that autoantibodies to collagen IX show diagnostic potential in early RA. However, no association was found between the antibody levels and outcome. Keywords: collagen type IX, extracellular matrix, integrins, rheumatoid arthritis Acknowledgements This work was carried out at the Collagen Research Unit of the Department of Medical Biochemistry and Molecular Biology, University of Oulu, and Biocenter Oulu, during the years 1999-2007. I wish to express my deepest gratitude to my supervisor, Professor Leena Ala- Kokko, for her encouragement, optimism and trust throughout these years. I would like to express my sincere thanks to Professors Kari Kivirikko, Taina Pihlajaniemi, Ilmo Hassinen and Johanna Myllyharju for providing excellent research facilities and creating a high-standard scientific environment as well as Professor Peppi Karppinen for leadership with a bright mind and tender heart. I wish to acknowledge all my co-authors. Tero Pihlajamaa is warmly acknowledged for his mentorship and collaboration during the early steps of my scientific career. Joni Ylöstalo also deserves my thanks for his cooperation. More recently, I have had the privilege to work with Professor David Hulmes, largely recognized for his expertise in collagen fibrillogenesis, Docent Jarmo Käpylä, an expert in the field of integrins, and Professor Markku Hakala as well as Docent Markku Kauppi and colleagues, specialists in clinical medicine, especially in rheumatoid arthritis. Docent Sohvi Hörkkö deserves my deepest gratitude for her continuous encouragement and positive attitude as well as expertise regarding the ELISA work and immunology in general. In this regard I am also grateful to Professor Riitta Karttunen for her help in providing the controls for the study. Professor Yrjö Konttinen and Docent Asta Pirskainen are gratefully recognized for their valuable comments on this thesis and Sandra Hänninen, M.Sc., for the careful revision of the language. Among the department personnel, I am especially grateful to Hongmin Tu who has always offered a helping hand when needed. Docent Minna Männikkö is warmly recognized not only for her support and good advice but also for open and relaxed conversations regarding any given subject. My warmest thanks belong also to Professor Johanna Myllyharju for her expert advice. I also want to thank Pertti Vuokila, Marja Leena Karjalainen, Marja-Leena Kivelä, Auli Kinnunen, Seppo Lähdesmäki and Risto Helminen for looking after the practical errands in the department. I want to express my dearest thanks to Helena Satulehto for all her efforts in the lab; they have been instrumental in achieving this goal. Thanks also to the other technicians in our group, including Aira Harju and especially Minta Lumme, with whom I had many enjoyable conversations. Thanks to Eveliina 5 Jakkula and Olli-Pekka Kämäräinen for sharing their room and their thoughts. Thanks for many interesting conversations and companionship with Heini, Marja, Iita, Merja, and Mirka. Thanks also to other members of the group, both former and current, who are not mentioned by name. I thank Anne Heikkinen, Eveliina Jakkula, Tero Pihlajaniemi and Jarmo Käpylä for their contribution to the tables and figures appearing in the text. I am also grateful to Marko Kervinen for his expertise in modifying figures into appropriate form. Above all, I wish to thank my parents for their never-ending love and support. Finally, I am grateful to my beloved wife, Minna, for her love and understanding, and to our children – two little princesses who have melted my heart for good. This thesis work was supported financially by the Finnish Centre of Excellence Programme (2000-2005) of the Academy of Finland, the Finnish Cultural Foundation (Northern Osthrobotnian Fund), the Tyyni Tani Foundation and the Maud Kuistila Foundation. Oulu, September 7, 2007 Juha Jäälinoja 6 Abbreviations BM basement membrane CCP cyclic citrullinated protein CIA collagen-induced arthritis CIX collagen IX COL collagenous domain COMP cartilage oligomeric matrix protein CRP C-reactive protein DMARD disease-modifying anti-rheumatic drug ELISA enzyme-linked immunosorbent assay ESR erythrocyte sedimentation rate FACIT fibril associated collagen with interrupted triple helices FcγR Fc gamma receptor GAG glycosaminoglycan IC immune complex IDD intervertebral disc disease Ig immunoglobulin IL interleukin MED multiple epiphyseal dysplasia MHC major histocompatibility complex MMP matrix metalloproteinase NC noncollagenous domain OA osteoarthritis PCR polymerase chain reaction PDI protein disulphide isomerase PPI peptidyl proline cis/trans isomerase RA rheumatoid arthritis rCIX recombinant human collagen IX RF rheumatoid factor SLRP small leucine-rich repeat proteoglycans TNFα tumor necrosis factor alpha vWFA von Willebrand factor A-like domain X or Y (in Gly-X-Y) any amino acid 7 8 List of original articles This thesis is based on the following articles which are referred to in the text by their Roman numerals: I Jäälinoja J, Ylöstalo J, Beckett W, Hulmes DJS & Ala-Kokko L (2007) Trimerization of collagen IX α chains does not require the presence of the COL1 and NC1 domains. Biochem J. In press. II Käpylä J, Jäälinoja J, Tulla M, Ylöstalo J, Nissinen L, Viitasalo T, Vehviläinen P, Marjomäki V, Nykvist P, Säämänen AM, Farndale RW,
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