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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
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 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.
xxii Introduction

BIOMARKES OF ENDOTHELIAL CELL DAMAGE

Exposure of the basement and interstitial membrane results in degradation products
DAMAGE, STRESS, AND
INFLAMMATORY CELLS
(A) (B1) CELL DEATH
(B2)
Epithelium
Epithelial cell

Basement membrane
Macrophage

Interstitial membrane
Fibroblast Myofibroblast
FIBROBLAST ACTIVATION

(C) TISSUE DAMAGE AND REPAIR BIOMARKERS (D1) TISSUE DAMAGE OF THE DEEP
INTERSTITIAL MEMBRANE
(D2) FIBROSIS
OF THE BASEMENT MEMBRANE

PROLIFERATION AND ACTIVATION OF FIBROBLASTS,

MIGRATION OF INFLAMMATORY CELLS

FIGURE 2 Schematic representation of the generation of biomarkers of endothelial or epi-

thelial cell damage from the basement and interstitial membranes. (A) Overview of the endo-
thelial cell layer which has well-organized basement and interstitial membranes below. (B) Cell
damage results in the death of localized epithelial cells, resulting in creation of myofibroblasts from
fibroblasts which proliferate and form a matrix (B1), followed by (B2) recruitment of inflammatory
cells such as macrophages through the damaged epithelium. (C) Continuous cell insult results in
tissue damage and denudation of the epithelium exposing the basement membrane to degradation
in which fragments of the basement membrane are released. (D) Deeper tissue damage exposes the
underlying interstitial membrane to degradation and its fragments are released through the basement
membrane (D1). Continuous inflammation load and activation of fibroblasts results in overproduc-
tion of components of the interstitial and basement membranes in an unorganized manner, ie, in
fibrosis (D2).

OVERALL STRUCTURE OF COLLAGENS

Collagens are widely expressed throughout all organs and tissues. They are
the most abundant proteins in connective tissue. To date, 42 different collagen
genes coding for 28 different types of collagens have been identified. Fig. 3
schematically displays the primary structure of the molecules. Collagens are
trimeric molecules composed of three polypeptide α-chains which contain the
repeated sequence (G–X–Y)n, X being frequently proline and Y hydroxypro-
line. These repeats allow the formation of a triple helix which is the characteris-
tic structural feature of the collagen superfamily. Each member of the collagen
family contains at least one triple-helical domain (COL) which is secreted and
deposited into the extracellular matrix (ECM). Most collagens are able to form
supramolecular aggregates. Besides triple-helical domains, collagens contain
 Introduction xxiii

non-triple-helical (NC) domains, used as building blocks by other ECM pro-

teins. The molecular structure and supramolecular assembly of collagens allow
their division into major subfamilies, depending on the supramolecular struc-
ture such as depicted in Fig. 4.

FIGURE 3 Schematic primary structure of collagen including depiction of functional

domains. Reproduced with permission from Ricard-Blum, S. The collagen family. Cold Spring
Harb Perspect Biol 2011;3:a004978.
xxiv Introduction

FIGURE 3 Cont’d
 Introduction xxv

FIGURE 4 The supermolecular structure of collagens. Reproduced with permission from Ricard-
Blum, S. The collagen family. Cold Spring Harb Perspect Biol 2011;3:a004978.

1. Fibril-forming collagens (I, II, III, V, XI, XXIV, XXVII);

2. Fibril-associated collagens with interrupted triple helices (FACITs) (IX,
XII, XIV, XVI, XIX, XX, XXI, XXII). The FACITs do not form fibrils by
themselves but they are associated with the surface of collagen fibrils.
3. Network-forming collagens (IV, VIII, X) form a pattern in which four mol-
ecules assemble via their amino-terminal 7S domain to form tetramers while
two molecules assemble via their carboxy-terminal NC1 domain to form
NC1 dimers
4. Membrane collagens (XIII, XVII, XXIII, XXV)

COLLAGEN SYNTHESIS AND OTHER ESSENTIALS

Collagens such as type 1 collagen are synthesized in the endoplasmic reticulum
where two pro-α1 chains and one pro-α2 combine to form procollagen. This
complex process j = is mediated by hydroxylation of prolines and lysines to sta-
bilize the helix, secretion to the extracellular space, enzymatic removal of the
N- and C-terminal propeptides, packaging the material into fibrils, and finally
the formation of inter-molecular cross-links leading to the final and mechani-
cally competent collagen fibrils. Further details on the molecular aspects of
this process are outside the scope of this article, but we refer the reader to Refs.
[19,20].
Extensive research has been conducted into the biosynthesis of fibril-form-
ing collagens that are synthesized as procollagen molecules comprised of an
amino-terminal propeptide followed by a short, nonhelical, N-telopeptide, a cen-
tral triple helix, a C-telopeptide and a carboxy-terminal propeptide. Individual
xxvi Introduction

procollagen chains are subjected to numerous post-translational modifications.

The heat shock protein 47 (HSP47) binds to procollagen in the endoplasmic
reticulum. HSP47 is a specific molecular chaperone of procollagen [21]. The
stabilization of the procollagen triple helix at body temperature requires the
binding of more than 20 HSP47 molecules per triple helix [22]. It has been sug-
gested recently that intracellular Secreted Protein Acidic and Rich in Cysteine
(SPARC) might be a collagen chaperone because it binds to the triple-helical
domain of procollagens and its absence leads to defects in collagen deposition
in tissues [23]. Both propeptides of procollagens are cleaved during the matura-
tion process. The N-propeptide is cleaved by procollagen N-proteinases belong-
ing to the A Disintegrin And Metalloproteinase with Thrombospondin Motifs
(ADAMTS) family, except the N-propeptide of the pro-a1(V) chain that is
cleaved by the procollagen C-proteinase, which is also termed Bone Morphoge-
netic Protein-1 (BMP-1) [24]. BMP-1 cleaves the carboxy-terminal propeptide
of procollagens except the carboxy-terminal propeptide of the pro-a1(V) chain,
which is processed by furin. The telopeptides contain the sites where cross-
linking occurs. This process is initiated by the oxidative deamination of lysyl
and hydroxylsyl residues catalyzed by the enzymes of the lysyl oxidase family.
The top part of the figure (above the cell membrane) (Fig. 5) illustrates the
intracellular events and the bottom part of the figure (below the cell membrane)
illustrates the extracellular events. During the synthesis of pro-α chains in the
endoplasmatic reticulum specific peptidyl lysine residues are hydroxylated to

FIGURE 5 Biosynthesis of collagen. Reproduced with permission from Yamauchi M, Sricholpech

M. Lysine post-translational modifications of collagen. Essays Biochem 2012;52:113–33.
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