Biochemistry of Collagens, Laminins and Elastin Structure, Function and Biomarkers Edited by Morten A. Karsdal Nordic Bioscience, Herlev, Denmark and Southern Danish University, Odense, Denmark Co-editors Diana J. Leeming Kim Henriksen Anne-Christine Bay-Jensen AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2016 Elsevier Inc. All rights reserved. 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Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-809847-9 For information on all Academic Press publications visit our website at https://www.elsevier.com/ Publisher: Sara Tenney Acquisition Editor: Jill Leonard Editorial Project Manager: Fenton Coulthurst Production Project Manager: Edward Taylor Designer: Christian Bilbow Typeset by TNQ Books and Journals List of Contributors A. Arvanitidis Nordic Bioscience, Herlev, Denmark C.L. Bager Nordic Bioscience, Herlev, Denmark A.C. Bay-Jensen Nordic Bioscience, Herlev, Denmark F. Genovese Nordic Bioscience, Herlev, Denmark N.S. Gudmann Nordic Bioscience, Herlev, Denmark D. Guldager Kring Rasmussen Nordic Bioscience, Herlev, Denmark N.U.B. Hansen Nordic Bioscience, Herlev, Denmark K. Henriksen Nordic Bioscience Biomarkers & Research, Herlev, Denmark Y. He Nordic Bioscience, Herlev, Denmark M.A. Karsdal ​ Nordic Bioscience, Herlev, Denmark S.N. Kehlet Nordic Bioscience, Herlev, Denmark N.G. Kjeld Nordic Bioscience, Herlev, Denmark J.H. Kristensen Nordic Bioscience, Herlev, Denmark; The Technical University of Denmark, Kongens Lyngby, Denmark D.J. Leeming Nordic Bioscience, Herlev, Denmark Y.Y. Luo Nordic Bioscience, Herlev, Denmark T. Manon-Jensen Nordic Bioscience, Herlev, Denmark J.H. Mortensen Nordic Bioscience, Herlev, Denmark M.J. Nielsen Nordic Bioscience, Herlev, Denmark S.H. Nielsen Nordic Bioscience, Herlev, Denmark J.M.B. Sand Nordic Bioscience, Herlev, Denmark A.S. Siebuhr Nordic Bioscience, Herlev, Denmark S. Sun Nordic Bioscience, Herlev, Denmark N. Willumsen Nordic Bioscience, Herlev, Denmark xi Preface This book on extracellular matrix (ECM) proteins is the result of appreciation and awe for matrix biology and structural proteins. These proteins are emerging as much more than passive bystanders to the fascinating life, death, and fate of cells: they control these cells. Many researchers and their important work have been cited in this book; however, not all, and not all who deserve to be cited are included. Thus, for all who are working on collagens, laminins, and elastin, please send your refer- ences and a summary of your work to be included in future editions of this book. The aspiration of these books on the ECM is to be as complete as possible regarding research on collagen biomarkers and their biology. Please contribute to this ongoing aspiration. The functions of many collagens still remain to be discovered and presented, both with respect to their physiological and pathophysiological roles. The hope of this book, and subsequent books, is to inspire new researchers to take the col- lagen challenge and present novel research and biology that are important for understanding the role of the ECM in pathological and physiological conditions. Sincerely Morten A. Karsdal, MSc, PhD, mBMA Professor, University of Southern Denmark xiii Acknowledgments I thank Claus Christiansen for discovering, developing, and validating (via the Food and Drug Administration) the first biomarker of the extracellular matrix (C-terminal telopeptide of type I collagen (CTX-I)). This fragment is a neo- epitope of type I collagen generated by proteolytic activity of cathepsin K, and is now recognized as the standard bone resorption marker. This discovery has inspired many researchers, including me, to discover, develop, and validate bio- markers of the ECM. Claus has always inspired us to do crazy, impossible, but focused science, with the goal of providing research that is applicable to many fields and researchers, to forward science. I thank all past and current PhD students as well as senior researchers that have helped me with understanding and quantifying the matrix. Without your dedication and hard work in generating data and conducting assays, this book would have been impossible. Special thanks are extended to the excellent tech- nical help in generating novel and critical assays of the matrix and for meticu- lous sample measurements. This book is truly a team effort of a large group of ECM researchers, all of whom are dedicated to quantifying and understanding the matrix in both patho- logical and physiological conditions. Thank you all for the help with this book. Most importantly, I thank all former and current collaborators who provided samples and engaged in discussions that helped in understanding the role of the ECM in connective tissue biology. Lastly, I thank the Danish Research Foundation for making it possible to write this book through the support of PhD programs, research on the ECM and biomarkers, and excellence in science. Sincerely Morten A. Karsdal xv List of Abbreviations 97-LAD 97-kDa linear IgA dermatosis antigen aa Amino acid ADAM A disintegrin and metalloproteinase ANCA Antineutrophil cytoplasmic antibodies APP Amyloid precursor protein ASPD Antisocial personality disorder BACE1 β-site APP-cleaving enzyme 1 bFGF Basic fibroblast growth factor BM Bethlem myopathy BMP-1 Bone morphogenetic protein 1 BMZ Basement membrane zone BP180 180-kDa bullous pemphigoid antigen BP230 230-kDa bullous pemphigoid antigen C5M Matrix metalloproteinase fragment of type V collagen CCDD Congenital cranial dysinnervation disorder CIA Collagen-induced arthritis CLAC Collagen-like amyloidogenic component COL Collagenous domain COPD Chronic obstructive pulmonary disease DDR1 Discoidin domain receptor 1 DMD Duchenne muscular dystrophy ECM Extracellular matrix EDS Ehlers–Danlos syndrome eGFR Estimated glomerular filtration rate ELISA Enzyme-linked immunosorbent assay EMI Emilin EMID2 Emilin/multimerin domain–containing protein 2 FACIT Fibril-associated collagens with interrupted triple helices FN Fibronectin type III G Globular GBM Glomerular basement membrane HANAC Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps HGNC HUGO Gene Nomenclature Committee HNE Human neutrophil elastase HNSCC Squamous cell carcinoma of the head and neck HPLC-MS High-performance liquid chromatography–mass spectrometry HSGAG Heparan sulfate glycosaminoglycan IGFBP-5 Insulin-like growth factor binding protein-5 IHC Immunohistochemistry xvii xviii List of Abbreviations IPF Idiopathic pulmonary fibrosis ISEMF Intestinal subepithelial myofibroblasts JEB Junctional epidermolysis bullosa KO Knockout LAD-1 120-kDa linear IgA dermatosis antigen LG Laminin globular MI Myocardial infarction MIM Mendelian inheritance in man MMP Matrix metalloproteinases mRNA Messenger ribonucleic acid MTJ Myotendinous junctions NAG N-acetyl-β-d-glucosaminidase NC1 Noncollagenous 1 NF Nuclear factor NSCLC Non-small-cell lung carcinoma OA Osteoarthritis OSCC Oral squamous cell carcinoma P5CP C-terminal propeptide of type V collagen P5NP N-terminal propeptide of type V collagen PARP Proline-arginine–rich protein PDGF Platelet-derived growth factor Pro-C5 Neoepitope of the C-terminal propeptide of type V collagen SNP Single nucleotide polymorphism SVAS Supravalvular aortic stenosis TACE Tumor necrosis factor-α converting enzyme TCR T cell receptor Tgase Transglutaminase TGF-β Transforming growth factor-β TSP Thrombospondin TSPN Thrombospondin N-terminal-like domain TSPN-1 N-terminal domain of thrombospondin-1 UCMD Ullrich congenital muscular dystrophy vWF-A Type A domains of von Willebrand factor α1 α1 chain α2 α2 chain Introduction M.A. Karsdal1,2 1Nordic Bioscience, Herlev, Denmark; 2Southern Danish University, Odense, Denmark The backbone of tissues is composed of structural proteins such as collagens, laminins, and elastin. During tissue turnover, these proteins are formed and degraded in a tight equilibrium to ensure tissue health and homeostasis. Imbal- ances in these processes can result in fibrosis. Fibrosis can affect almost any organ or tissue. The core protein of fibrosis is collagen and other structural pro- teins such as laminins and elastin. Collagens are not simply structural in role: each has a unique expression pattern and some have key signaling functions in addition to their structural functions. The common denominator for collagens is the triple-helix structure, which is less pronounced in laminins. Collagens are divided into several distinct subgroups of which the fibrillar and networking collagens are the most investigated. This chapter introduces the superstructure of collagens, laminins, and elastin as well as key features of collagen biology, expression, and function. WHY ARE COLLAGENS AND STRUCTURAL PROTEINS IMPORTANT? Fibrosis can affect almost any organ or tissue. Fibrosis is characterized by the formation of excess connective tissue that damages the structure and function of the underlying organ or tissue and can lead to a wide variety of diseases. Fibro- sis can result either from injury to tissue, in which case it manifests as scarring, or from abnormal connective tissue turnover. Forty-five percent of all deaths in the developed world are associated with chronic fibroproliferative diseases [1,2] such as atherosclerosis and alcoholic liver disease. The common denominator of fibroproliferative diseases is dysreg- ulated tissue remodeling, leading to the excessive and abnormal accumulation of extracellular matrix (ECM) components in affected tissues [1,3–7]. This ECM has an altered structure and signals abnormally to the cells that are embedded in it [1–5]. During fibrosis, the composition of ECM proteins and their interactions with each other and with the cells that attach to them are altered [1,7,8]. Fibrosis can affect almost any organ or tissue. Fig. 1 illustrates the major fibroproliferative diseases with a significant impact on human health [1,4,7–9]. xix xx Introduction FIGURE 1 Examples of fibroproliferative diseases in different organs. AMD, age-related mac- ular degeneration; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmo- nary disease; IPF, idiopathic pulmonary fibrosis; NASH, nonalcoholic steatohepatitis. Reproduced with permission from Karsdal MA, Krarup H, Sand JM, Christensen PB, Gerstoft J, Leeming, DJ, et al. Review article: the efficacy of biomarkers in chronic fibroproliferative diseases – early diag- nosis and prognosis, with liver fibrosis as an exemplar. Aliment Pharmacol Ther 2014;40:233– 49 and Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand, JM, et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2015. Fibrotic tissue was has long been considered an inactive scaffold, prevent- ing regeneration of the affected organ. However, this perception cannot be upheld because fibrosis is neither static nor irreversible, but instead the result of a continuous remodeling that makes it susceptible to intervention [1,10,11]. The major future challenge in fibrosis will be to halt fibrogenesis and reverse advanced fibrosis without affecting tissue homeostasis or interfering with nor- mal wound healing. Consequently, our increased understanding of the ECM, its dynamics, and the potential of fibrotic microenvironments to reverse holds promise for the development of highly specific antifibrotic therapies with mini- mal side effects. Traditionally, only growth factors, cytokines, hormones, and certain other small molecules have been considered as relevant mediators of inter-, para-, and intracellular communication and signaling. However, the ECM fulfils direct Introduction xxi and indirect paracrine or even endocrine roles. In addition to maintaining the structure of tissues, the ECM has properties that directly signal to cells. Even conceptually exclusively structural proteins such as fibrillar collagens or pro- teoglycans are emerging as specific signaling molecules that affect cell behavior and phenotype via cellular ECM receptors. In addition, the ECM can bind sev- eralfold to otherwise soluble proteins, growth factors, cytokines, chemokines, or enzymes, thereby restricting or regulating their access to cells as well as spe- cifically attracting and modulating the cells that produce these factors. More- over, specific proteolysis can generate biologically active fragments from the ECM, while the parent molecules of the ECM are inactive. The ECM thus can control cell phenotype by functioning as a precursor bank of potent signaling fragments in addition to having a direct effect on cell phenotype through ECM– cell interactions mediated by receptors such as integrins, certain proteoglycans, or both [12–14]. The aims of this book are to (1) summarize all current data on key structural proteins of the ECM (ie, collagens, laminins, and elastin); (2) review how these molecules affect pathologies, in part, exemplified by monogenetic disorders; (3) describe selected posttranslational modifications (PTMs) of ECM proteins that result in altered signaling properties of the original ECM component; (4) discuss the novel concept that an increasing number of components of the ECM harbor cryptic signaling functions that may be viewed as endocrine functions; and (5) highlight how this knowledge can be exploited to modulate fibrotic disease. INTRODUCTION TO THE MATRIX-INTERSTITIAL AND BASEMENT MEMBRANES When tissue is injured, endothelial or epithelial cells on the tissue surface are destroyed, exposing the basement membrane to degradation and an influx of inflammatory cells and the deeper interstitial membrane to the risk of fibrosis (Fig. 2). The main constituents of the basement membrane are type IV colla- gen, laminin, and nidogen. Fragments of type IV collagen—tumstatin—have been shown to be very antiangiogenic, possibly directing recovery of the epi- thelium by allowing horizontal growth over the basement membrane rather than uncontrolled vertical growth into the basement and interstitial membranes. In the interstitial membrane, other collagens such as type XVIII are present. A protease-derived fragment of collagen type XVIII, endostatin [17], is the most potent natural anti-angiogenic molecule which has been show to block fibrosis in fibrotic models of the liver and lung. Other collagens such has type XV may play similar or more tissue-specific roles by releasing active protein fragments (called neoepitopes) such as restin, although this needs to be fully investigated [16]. During repair of the matrix after epithelial damage, the underlying mem- branes are destroyed by proteases, giving rise to new signaling molecules that may be both antifibrogenic and antiangiogenic and could potentially have other functions that are yet to be discovered.