Biologia de La Matrix Extracelular PDF

ATROPHIES AND DISORDERS OF DERMAL CONNECTIVE TISSUES SECTION 15
Leena Bruckner-Tuderman
Key features
Extracellular matrices (ECMs) represent specifically organized
networks of collagens, elastin, glycoproteins and proteoglycans
that have distinct structural roles and specific functional properties
in all tissues
ECMs are biologically active, interact with cells, and regulate
cellular functions during development, regeneration and normal
tissue turnover
Mutations in genes encoding ECM proteins cause a broad
spectrum of human diseases, from EhlersDanlos syndrome to
epidermolysis bullosa, and components of the ECM are targeted in
autoimmune diseases such as bullous pemphigoid, epidermolysis
bullosa acquisita and lichen sclerosus
The collagen family contains 28 different subtypes. All collagens
consist of three polypeptide -chains, which are folded into a
triple helix. In each chain, every third amino acid is glycine (Gly),
and thus a sequence of an -chain can be expressed as (Gly-X-Y)n.
A hallmark of collagens is the presence of hydroxyproline (Hyp) in
the Y position of this repeat sequence. Collagens are expressed in
all tissues of the human body, and distinct sets of collagens
co-polymerize into highly organized suprastructures, e.g. fibrils
and filaments, in a tissue-specific manner
Elastin provides tissues with their elasticity. Elastin monomers
contain repetitive hydrophobic sequences and are highly crosslinked. The cross-links between several individual molecules
provide for both elasticity and insolubility of the elastic fibers,
which can be stretched by 100% or more and still return to their
original form. In addition to elastin, elastic fibers in the dermis also
contain a microfibrillar component that attaches the fibers to the
surrounding structures
INTRODUCTION
The different types of extracellular matrix (ECM) represent specifically
organized assemblies of the macromolecules listed in Table 95.1. The
macromolecules have characteristic patterns of aggregation into insoluble suprastructures with a high degree of order at successive hierarchic
levels1. Each of these structures is tissue-specific and adapted to the
particular needs of a given tissue. At first glance, the major constituents
are often similar in functionally diverse ECMs. However, different types
of quantitatively minor molecular components associate with major
elements in tissue-specific suprastructural arrays determined by their
relative compositions. The matrix suprastructures may be likened to
alloys, each having metallurgic properties that differ from each other
and those of the pure metals (Fig. 95.1).
Individual ECM macromolecules are usually oligomers composed of
one or several polypeptides. Intimate contacts between the subunits are
formed by coiled-coil structures, such as the collagen triple helix or
supercoiled -helices comprised of three or more polypeptides. In addition, large matrix macromolecules can be regarded as linear sequences
of structural modules that are similar in a large variety of proteins1.
The modules can be recognized by several cellular receptors, but receptor clustering is determined in a tissue-specific manner and the response
may be different in different tissues.
95
Our knowledge of ECM macromolecules has expanded dramatically

in recent years due to the great power of both molecular genetics and
proteomics. A multitude of molecules have been characterized and their
expression, regulation, tissue specificity and functions discerned2. The
assembled ECM structures are generally adhesive, enabling the attachment of tissue-specific cells, leukocytes, tumor cells, and even microorganisms. Through integrin-mediated interactions with cells, matrix
molecules control cell proliferation, differentiation and migration, especially during development and regenerative processes. Without contact
with the ECM, many cells undergo apoptosis. Furthermore, the ECM
can function as a reservoir of information; certain proteoglycans and
proteins bind growth factors (e.g. transforming growth factor [TGF]-)
and release and activate them as needed to control cellular functions2.
To date, mutations in approximately 50 different genes encoding ECM
molecules have been found to underlie heritable disorders in humans
and mice.
CHAPTER
95
Biology of the Extracellular Matrix
STRUCTURE AND FUNCTION OF THE

EXTRACELLULAR MATRIX
Collagens
The collagen family of proteins plays an important role in maintaining
the integrity of most tissues. The family currently includes 28 proteins
formally defined as collagens3 (Table 95.2). These proteins contain at
least 43 distinct polypeptide chains, each encoded by a different gene,
and more than 15 other proteins have a collagen-like domain (e.g.
macrophage scavenger receptor 1 and 2, ectodysplasin, pulmonary surfactant proteins).
Collagen triple helix

All collagens consist of three polypeptide chains, known as -chains,
which are folded into a triple helix. In some collagens, the -chains are
identical (homotrimers), while others contain two or three different
-chains (heterotrimers). In each polypeptide chain, every third amino
acid is glycine (Gly), and the sequence of an -chain can be expressed
as (Gly-X-Y)n, where X and Y represent other amino acids and n varies
according to the length of the -chain. A high number of proline (Pro)
and hydroxyproline (Hyp) residues are in the X and Y positions, respectively, and hydrogen bonds between the hydroxyl groups of Hyp contribute to the stability of the helix. The prototype collagen (type I) has
an uninterrupted Gly-X-Y repeat sequence that is almost 1000 amino
acid residues in length. This forms a rigid, rod-like structure with a
diameter of 1.5nm and length of 300nm. In some collagens, the (GlyX-Y)n repeats are interrupted by one or more amino acids. The interruptions may be numerous and longer than the (Gly-X-Y)n repeats, and
they provide the molecule with flexibility, which is important for the
specific functions of a given collagen type3.
Biosynthesis of collagens
Collagen biosynthesis involves a number of post-translational modifications (Fig. 95.2). Some collagens are first synthesized as procollagens
that have propeptide extensions at their N-terminus, their C-terminus,
or both termini. The main intracellular steps in collagen biosynthesis
include the following:
cleavage of signal peptides
hydroxylation of certain Pro and lysine (Lys) residues to 4-Hyp,
3-Hyp, and hydroxylysine (Hyl)
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COMPONENTS OF THE EXTRACELLULAR MATRIX
SECTION
Atrophies and Disorders of Dermal Connective Tissues
15
BIOSYNTHESIS OF A PROTOTYPE COLLAGEN
Laminins (18)**
Proteoglycans (Table 95.3)
Glycoproteins (Table 95.4)
Integrins
Modifying enzymes
Collagens (28 types)

Elastin
Fibrillins (3 types)
LTBPs (4 types)
Fibulins* (7 types)
*Fibulins are believed to function as intra-molecular bridges that stabilize ECM structural
networks (e.g. elastic fibers, microfibrils or basement membrane structures).
**15 of which are well characterized.
OH
OH
EDS,
kyphoscoliosis
type (VI)
Table 95.1 Components of the extracellular matrix (ECM). These belong to

several protein superfamilies. The molecules assemble into mixed fibrils and
networks in a tissue-specific manner. Several enzymes are involved in the
biosynthesis and modification of ECM assemblies. Integrins are the main
cellular receptors for the ECM. LTBP, latent TGF- binding protein.
OH
OH
OH
OH
OH
OH
OH
Hydroxylation
(requires vitamin C)
Lysyl
hydroxylase
Prolyl
hydroxylase
Glycosylation
O Gal Glc
Glc
Gal
O
OH
OH
OH
OH
(Man)n
GlcNAc
OH
DERMAL EXTRACELLULAR MATRIX NETWORKS

OH
Elastic
fibers
OH
Microfibrils
OH
OH
O
Gal
C
Procollagen
N
Intracellular
Extracellular
Fibroblast
*
EDS,
dermatosparaxis
type
(VIIC)
Mixed fibrils containing
collagens I, III, V,
minor collagens,
and proteoglycans
Fig. 95.1 Dermal extracellular matrix networks. Different molecules

polymerize into distinct fibril networks and, within the mesh of the networks,
cells are embedded in the amorphous extrafibrillar matrix. The fibril networks
interact with each other, with the extrafibrillar matrix and with the cells. These
networks have a dual function: support of the tissue and regulation of cellular
functions.
1586
glycosylation of some of the Hyl residues to galactosyl-Hyl and

glucosylgalactosyl-Hyl
glycosylation of certain asparagine residues
association of the -chains in a specific manner
formation of intra- and interchain disulfide bonds
folding of the triple helix.
After the chains have become associated and sufficient Hyp residues
have been formed in each chain, a nucleus of the triple helix forms
(usually in the C-terminal region) and propagates towards the other
end of the molecule in a zipper-like fashion4. The procollagen molecules
are then transported from the endoplasmic reticulum across the Golgi
apparatus without leaving the lumen of the Golgi cisternae. During this
transport, the molecules begin to aggregate laterally and form early
fibrils ready for secretion5. The extracellular steps in biosynthesis
typically include cleavage of the N- and/or C-terminal propeptides,
assembly into suprastructures with other collagens and non-collagenous
components, and formation of covalent cross-links.
The specific enzymes involved in the biosynthesis of collagens include
prolyl-4-hydroxylase and prolyl-3-hydroxylase, which hydroxylate Pro
Procollagen N-proteinase
Procollagen C-proteinase
Collagen
Lysyl oxidase
(requires copper)
Mixed
fibril
(crosslinked)
* Persistence of this form due to mutations that eliminate cleavage site EDS, arthrochalasia
type (VIIA, B)
Fig. 95.2 Biosynthesis of a prototype collagen. The procollagen -chains

are synthesized in the rough endoplasmic reticulum. During its synthesis,
certain prolyl and lysyl residues on the nascent polypeptide are hydroxylated
and modified by glycosylation. Three -chains associate to form a trimer and
fold into a triple helix. The newly formed triple helical procollagen is secreted
into the extracellular space, where the N- and C-terminal propeptides are
cleaved by specific proteases. The mature collagen molecules assemble to form
mixed fibrils with other collagens and non-collagenous molecules. The
suprastructures are stabilized by covalent cross-links. EDS, EhlersDanlos
syndrome. Adapted from Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations
in humans, flies and worms. Trends Genet. 2004;20:3343.
residues to Hyp, and lysyl hydroxylases, which hydroxylate Lys residues

to Hyl. These enzymes require O2, Fe2+, -ketoglutarate and ascorbate
(vitamin C) as cofactors for the reactions. In the rough endoplasmic
reticulum, glycosyltransferases add glucosylgalactosyl disaccharides
onto the -chains. The same intracellular enzymes modify all collagen

Type
Chains
Gene
Tissue distribution
FIBRIL-FORMING COLLAGENS
Collagen I
Collagen II
Collagen III
1(I), 2(I)
1(II)
1(III)
COL1A1, COL1A2
COL2A1
COL3A1
Collagen V
1(V), 2(V), 3(V)
Collagen XI
1(XI), 2(XI), 3(XI)
Collagen XXIV*
Collagen XXVII*
1(XXIV)
1(XXVII)
COL5A1, COL5A2,
COL5A3
COL11A1,
COL11A2,
COL11A3
COL24A1
COL27A1
Skin, most ECM

Cartilage, vitreous humor
Skin (including fetal skin), lung,
vasculature
Skin, with collagen I heterotypic fibrils
Table 95.2 The collagen family of proteins. The

names of types found in the skin are in bold italics.
Multiplexins are collagens with multiple triple helix
domains and interruptions. ECM, extracellular
matrix; FACITs, fibril-associated collagens with
interrupted triple helices.
With collagen II heterotypic fibrils

Developing bone and cornea
Cartilage, eye, ear, lung
FACITS
Collagen IX
1(IX), 2(IX), 3(IX)
Collagen XII
Collagen XIV
Collagen XVI
Collagen XIX
Collagen XX
Collagen XXI
Collagen XXII*
1(XII)
1(XIV)
1(XVI)
1(XIX)
1(XX)
1(XXI)
1(XXII)
Collagen XXVI*
1(XXVI)
COL9A1, COL9A2,
COL9A3
COL12A1
COL14A1
COL16A1
COL19A1
COL20A1
COL21A1
COL22A1
COL26A1
With collagen II heterotypic fibrils

Skin, tissues containing collagen I
Skin, tissues containing collagen I
Skin, many tissues
Basement membranes, fetal muscle
Skin, cornea, cartilage, tendon
Many tissues, including skin
Tissue junctions (including between the
anagen hair follicle and dermis)
Testis, ovary
CHAPTER
95
THE COLLAGEN FAMILY OF PROTEINS
BASEMENT MEMBRANE COLLAGENS

Collagen IV
1(IV), 2(IV), 3(IV),

4(IV), 5(IV), 6(IV)
COL4A1, COL4A2,
COL4A3,
COL4A4,
COL4A5, COL4A6
All basement membranes, isoforms vary

Skin: 1(IV), 2(IV), 5(IV) and 6(IV)
MICROFIBRILLAR COLLAGENS
Collagen VI
1(VI), 2(VI), 3(VI)
COL6A1, COL6A2,
COL6A3
Skin, other microfibril-containing tissues
NETWORK-FORMING COLLAGENS
Collagen VIII
Collagen X
1(VIII), 2(VIII)
1(X)
Collagen VII
1(VII)
Collagen XIII
Collagen XVII
Collagen XXIII*
Collagen XXV*
1(XIII)
1(XVII)
1(XXIII)
1(XXV)
Collagen XV
Collagen XVIII
1(XV)
1(XVIII)
Collagen XXVIII
1(XXVIII)
COL8A1, COL8A2
COL10A1
Skin, subendothelial matrices

Hypertrophic cartilage
ANCHORING FIBRIL COLLAGEN

COL7A1
Skin, mucous membranes, cornea
TRANSMEMBRANE COLLAGENS
COL13A1
COL17A1
COL23A1
COL25A1
Skin, many tissues

Skin, mucous membranes, cornea
Lung, cornea, brain, skin, tendon, kidney
Brain, neurons
MULTIPLEXINS
COL15A1
COL18A1
Many tissues; parent molecule of restin

Many tissues, including skin,
subendothelial matrices; parent
molecule of endostatin
NOVEL COLLAGENS
COL28A1
Schwann cells; fetal skin and calvaria
*Classification based upon cDNA sequence.
Inhibitors of angiogenesis.
chains4. The extracellular processing enzymes have a higher substrate

specificity. Procollagen I N-proteinase cleaves the N-propeptide of procollagens I and II. This enzyme is a member of the disintegrin and
metalloproteinase (ADAM) proteinase family and is also designated as
ADAM with thrombospondin type 1 motif (ADAMTS)-2. Procollagen
C-proteinase cleaves the C-propeptide of collagens I, II, III, V and VII.
It is a member of the tolloid proteinase family and is also called bone
morphogenetic protein (BMP)-1, since it was initially co-purified with
other BMPs from bone extracts. Cross-linking between collagen molecules involves the -amino groups of Lys and Hyl and is catalyzed by
lysyl oxidase, a copper-requiring enzyme4. Another enzyme that catalyzes cross-linking of at least some collagens is tissue transglutaminase.
Collagen VII-containing anchoring fibrils in the upper dermis appear

to be transaminated, and collagen VII serves as a substrate for tissue
transglutaminase-2 in vitro6.
The collagen family of proteins

The length and continuity of the triple helical domains vary among the
collagen types. For practical purposes, the collagens have been divided
into groups according to their ability to form supramolecular aggregates,
which are depicted in Figure 95.3. The types and tissue distributions
of the collagens in each group are listed in Table 95.2, and those found
in the skin are discussed below. More detailed information on all the
collagen types is available in recent reviews1,35.

1587
-chains, which form three major networks: (1) 1/2-containing; (2)

3/4/5-containing; and (3) 1/2/5/6-containing3. In the skin, the
1/2-containing collagen IV network dominates within the dermal
epidermal junction (see Ch. 28), but the 1/2/5/6-containing network
is also thought to be present3. The chain composition is determined by
the carboxy-terminal non-collagenous (NC1) domains; covalent interactions between these domains link -chains to each other and have a
role in the formation of collagen IV dimers (composed of two triplehelical protomers). In addition, connections between amino-terminal
7S domains lead to formation of collagen IV tetramers (composed of
four triple helical protomers; see Figs 28.5 and 95.3).
Two collagens are essential for the cohesion of the epidermis and
dermis (see Ch. 28). Collagen VII is the major, if not sole, component
of the anchoring fibrils that attach the basement membrane to the
dermal ECM. Collagen XVII (also known as bullous pemphigoid antigen
2) is a component of the anchoring filaments that bind the basal keratinocytes to the lamina densa (basement membrane proper). It is a
transmembrane collagen in type II orientation with a long extracellular
C-terminal region containing a multiply-interrupted triple helix referred
to as collagenous domains 115 (see Fig. 31.9). The ectodomains can
be shed from the cell surface by transmembrane proteases7, a process
important for regulation of cell adhesion and migration. Basal
Collagens of the skin

SECTION
15
Collagens account for 75% of the dry weight and 2030% of the volume
of the dermis. Different collagens polymerize into distinct suprastructures and have specific functions in the dermis as well as in epidermal
and vascular basement membranes. Pure collagen fibrils do not exist;
these fibrils are always mixtures of several collagens and other molecules, e.g. proteoglycans1. Classic, ultrastructurally recognizable, crossbanded fibrils in the dermis contain collagens I, III, V, XII and XIV. The
characteristic cross-banding (Fig. 95.4) with periodicity of 64nm results
from precise lateral packing of the different collagens within the fibrils
(see Fig. 95.3). Collagen I is the major component of the fibrils, and
the amount of other collagens varies. For example, during embryonic
development and wound repair, the content of collagen III is higher
than in the steady-state situation. Of note, collagen III is also an important component of the vasculature, in particular arterial walls. Collagen
VI, a highly glycosylated and disulfide-bonded collagen, is a component
of almost all tissues, including the skin. In vitro, it polymerizes to form
beaded filaments (see Fig. 95.3), but in vivo in the dermis, the ultrastructure of the collagen VI fibrils is reminiscent of microfibrils.
The collagen IV molecules in different basement membranes are
composed of six genetically distinct but structurally homologous
SUPRAMOLECULAR ASSEMBLIES OF COLLAGENS

1. Fibril-forming collagens I, II, III, V, XI and
based upon gene structure, XXIV and XXVII
2. FACIT and related collagens IX, XII, XIV, XVI, XIX, XX,
XXI, XXII and XXVI
Triple helical region

N propeptide
IX
C propeptide
Type II
fibril
GAG
XII and XIV
100 nm
Type I
fibril
100 nm
300 nm
Fig. 95.3 Supramolecular assemblies of collagens.

The suprastructures formed by different collagens
are shown. Non-collagenous components also
interact with the fibrils and networks. The
suprastructural organization of the transmembrane
collagens XIII and XVII and the multiplexin collagens
XV and XVIII is not known yet (panels 7 and 8). These
collagens are in close vicinity to basement
membranes and are likely to participate and/or
interact with the different basement membrane
networks. FACIT, fibril-associated collagens with
interrupted triple helices; GAG, glycosaminoglycans.
Adapted from Myllyharju J, Kivirikko KI. Collagens, modifying enzymes
and their mutations in humans, flies and worms. Trends Genet.
2004;20:3343.
100 nm
3. Collagen IV family
4. Collagen VI forming beaded filaments
7S
VI
Dimer
100 nm
100 nm
Dimer
100 nm
Tetramer
200 nm
5. Collagens forming hexagonal

networks VIII and X
Basement membrane
network
Tetramer
Beaded filament
6. Anchoring fibril collagen VII

Dimer
VII
VIII
200 nm
100 nm
Anchoring fibril
100 nm
100 nm
Basement
membrane
7. Collagens with transmembrane
domains XIII, XVII, XXIII and XXV
8. Multiplexin collagens XV and XVIII
XIII
XV
XVII
XVIII
100 nm
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GAG
= transmembrane
domains
Anchoring
plaque
7S = domain involved
in tetramerization
Restin
Endostatin
100 nm
N and C-terminal
non-collagenous domains
Non-collagenous domains
interrupting the triple helix

are associated with abnormalities of skin collagens or the enzymes that

process them (see Tables 95.5 & 95.6, and discussion below).
Elastic Fibers
The elasticity of many tissues, including the skin, depends upon the
structure of elastic fibers, which can have variable compositions. A
characteristic property of these fibers is that they can be stretched by
100% or more and still return to their original form. The main components of elastic fibers are elastin and microfibrils.
Elastin
Elastin is a highly cross-linked protein8. Its monomer, tropoelastin,
contains repetitive modules of hydrophobic amino acids (Val-Gly-ValPro-Gly)n and exists in several tissue-specific splice variants. Ala- and
Lys-rich repeats form critical cross-linking domains and may interrupt
the basic repetitive structure. Lysyl oxidase, the same copper-dependent
enzyme that catalyzes collagen cross-linking (see above), catalyzes the
formation of desmosine cross-links between elastin molecules, which
account for both the elasticity and insolubility of elastic fibers. Although
elastin makes up the bulk of mature elastic fibers, the precise interactions between microfibrils and elastin that occur during elastic fiber
assembly are not currently known. A current model based on coordinated, spatially and temporally regulated assembly is presented in
Figure 95.5.
CHAPTER
95
keratinocytes also express a second transmembrane collagen, type XIII,

which is a component of focal contacts.
The vascular basement membranes in the skin contain yet other
collagens namely, collagens VIII and XVIII. Collagen VIII builds
hexagonal networks below the endothelial basement membranes
(see Fig. 95.3) and, thus, structurally strengthens the vascular wall.
Collagen XVIII is localized at the dermal side of vascular basement
membranes. Its C-terminal fragment, endostatin (see Fig. 95.3), is
proteolytically released from the collagen molecule and has independent biological functions that include inhibition of angiogenesis3.
Most collagens in the skin are products of dermal fibroblasts. Exceptions include: (1) collagen XVII, a surface component of epidermal
keratinocytes; (2) collagen VII, which can be synthesized by both
keratinocytes and fibroblasts; and (3) collagens VIII and XVIII, which
are produced by endothelial cells. Several genetic and acquired diseases
Microfibrils
Fig. 95.4 Fibrillar and filamentous networks extracted from human skin. The
large cross-banded fibrils represent dermal mixed fibrils containing collagens I,
III and V; other minor collagens; and decorin (a proteoglycan). The crossbanding has a characteristic periodicity of 64nm. The filamentous network in
the background contains microfibrillar and basement membrane components.
In this immunoelectron photomicrograph, the black dots are colloidal gold
particles coupled to anti-collagen IV antibodies, indicating that basement
membrane networks are strongly associated with the dermal fibrillar networks.
Courtesy, Uwe Hansen, MD.
Microfibrils (10 to 12nm in diameter) insert into the basement membrane in a perpendicular orientation (classically referred to as oxytalan
fibers) and extend into the papillary dermis (Fig. 95.6), where they
gradually merge with elastic fibers that contain a relatively small
amount of elastin and form a plexus parallel to the dermalepidermal
junction (classically referred to as elaunin fibers). Such fibers appear
to be continuous with the elastic fibers within the reticular dermis,
which contain more abundant elastin. Microfibrils consist mainly of
fibrillins9, but they also contain and associate with other proteins, such
as microfibril-associated glycoproteins (MAGPs), latent TGF- binding
proteins (LTBPs), fibulins, elastin microfibril interfacer (EMILIN)-1
and, in the papillary dermis, collagen XVI8,9. Fibrillins 13 are large
glycoproteins that contain both epidermal growth factor (EGF) and
cysteine (Cys) repeats. The EGF repeats bind calcium, which is required
for stabilization of the protein. Fibrillin-1 interacts with perlecan in the
epidermal basement membrane to attach the microfibrils to the dermal
epidermal junction.
A new paradigm has emerged from recent investigations demonstrating that, in addition to guiding elastic fiber assembly and providing
structural support, fibrillins function together with LTBPs to regulate
cell signaling10. The four members of the LTBP family are highmolecular-weight glycoproteins characterized by EGF-like and 8-Cys
repeats, and they all associate with the small latent complex of TGF-
ELASTIC FIBER ASSEMBLY
Cutis laxa,
AR > AD
4
2
Extracellular
Lysyl oxidase
Intracellular
Marfan
syndrome
Lysyl oxidase
Integrins
Cutis laxa,
AD > AR
Tropoelastin
Desmosine cross-link
Fibulin-4 and -5
Fibrillin 1-containing microfibril
Microfibril-associated glycoprotein
Fig. 95.5 Elastic fiber assembly. This model is based

on current knowledge of interactions between
elastin, microfibrillar proteins and cells in generating
a functional elastic fiber. Tropoelastin is secreted and
cross-linked by lysyl oxidase on the cell surface (1).
Additional elastin is added to the aggregates (2),
which are then transferred onto pre-existing
fibrillin-1-containing microfibrils (3) that bind to the
cell surface via integrins. Fibulin-4 and -5 interact
with the elastin aggregates, enhance cross-linking
and bind to fibrillin-1, thus augmenting the transfer
of elastin aggregates to the microfibrils. The elastin
aggregates and the microfibrils develop into larger
structures (4) and are further cross-linked by lysyl
oxidase (5) to form a functional elastic fiber. Adapted
from Wagenseil JE, Mecham RP. New insights into elastic fiber assembly.
Birth Defects Res C Embryo Today. 2007;81:22940.

1589
Fig. 95.6 Microfibrils in

the papillary dermis.
Confocal scanning
microscopy of
microfibrils, which
emerge from the
epidermal basement
membrane and traverse
the papillary dermis
perpendicularly. The
immunostaining is with
antibodies to fibrillin-1
(red) and latent TGF-
complex (green). The
orangeyellow color
demonstrates
co-localization of both
proteins on the
microfibrils.
SECTION
15
Courtesy, Michael Raghunath, MD. See also Raghunath M, Unsld C, Kubitscheck U, etal. The cutaneous
microfibrillar apparatus contains latent transforming growth factor-beta binding protein-1 (LTBP-1) and is
a repository for latent TGF-beta1. J Invest Dermatol. 1998;111:55964.
(see below; Fig. 95.7). The LTBP-1/latent TGF- complex (referred to

as the large latent complex) binds to fibrillin-containing microfibrils.
Together, they control bioavailability of TGF- in the skin and other
tissues. LTBPs contain multiple proteinase-sensitive sites, providing the
means to solubilize the large latent complex from ECM structures, and
both soluble and ECM-associated forms are known to exist. Another
group of signaling molecules that can bind to fibrillins are the bone
morphogenetic proteins (BMPs)10. These are secreted as cross-linked
dimeric complexes that are associated through their prodomains, which
interact directly with the amino-terminus of fibrillin. Fibrillins and
LTBPs therefore have important roles in targeting latent, activatable
TGF- and BMPs into different ECMs. Thus, microfibrils serve not
only as a force-bearing element and scaffolding for elastin deposition
in the dermis, but also as an important repository for signaling molecules in the skin2,9,10.
The Extrafibrillar Matrix
1590
The dermal fibril networks and cells are embedded in an amorphous

extrafibrillar material that binds water and provides the hydrated consistency of the skin. Previously, this amorphous material was presumed
to be biologically unstructured and inert and was called the ground
substance. This prediction turned out to be incorrect the extrafibrillar matrix is molecularly and structurally diverse, highly organized, and
biologically active. It contains a number of proteoglycans and glycoproteins as well as hyaluronic acid and water. The functions of the extra
fibrillar matrix are adapted to the biologic needs of each tissue. For
example, during embryonic development, water-binding proteoglycans
and glycosaminoglycans (GAGs) form a hydrated milieu for cell migration and proliferation. During development and tissue remodeling,
glycoproteins of the extrafibrillar matrix are essential for formation of
the correct tissue architecture.
GAGs are polysaccharides composed of sulfated and acetylated sugars
with negative charges that can bind large amounts of ions and water.
The most prominent and ubiquitous protein-free GAG is hyaluronic
acid, a giant polysaccharide composed of thousands of Nacetylglucosamine/glucuronic acid disaccharides. Other GAGs, however,
bind to proteins with a serine hydroxyl group, forming a proteoglycan
(Fig. 95.8)11. Proteoglycans differ remarkably in their protein content
and the number, type and length of their GAG side chains (Table 95.3).
Four different proteoglycan-bound GAGs are known: chondroitin
sulfate, dermatan sulfate, keratan sulfate and heparan sulfate11. Versican is the most important proteoglycan in the dermis (see Fig. 95.8).
It is associated with the elastic fiber system and forms huge complexes
with hyaluronic acid, which provide the skin with its tautness. Versican
can be synthesized by fibroblasts, smooth muscle cells and epithelial
cells.
Perlecan is a major heparan sulfate proteoglycan found in all basement membranes, including the epidermal basement membrane12.
Small leucine-rich proteoglycans (SLRPs) are characterized by a protein
core of Leu-rich repeats and Cys-bonded loops, with only one or two
GAG chains. SLRPs that are found in the skin include decorin, biglycan,
fibromodulin, lumican and keratocan11. Decorin has multiple functions; for example, it binds to collagen fibrils and TGF-. Biglycan is a
cell surface proteoglycan that also binds to TGF-, and fibromodulin
regulates formation of collagen-containing fibrils. Syndecans are transmembrane heparan sulfate proteoglycans that regulate cell adhesion to
the ECM and subsequent cytoskeletal organization. Syndecans 1, 2 and
4 are expressed in the skin and can be found in keratinocytes, dendritic
cells and fibroblasts, where they are thought to mediate outside-in
cell signaling11.
Laminins and Other Glycoproteins

Laminins, a family of basement membrane glycoproteins with 18
members (three of which are not yet well characterized), are expressed
in all tissues. Each laminin isoform is a trimer consisting of an -, and -chain13,14. The current laminin nomenclature (revised in 2005) is
based on the chain composition, e.g. the laminin isoform that is composed of 3-, 3- and 2-chains is referred to as laminin 332 (formerly
known as laminin 5)15. In the skin, the epidermal basement membrane
contains laminins 332, 311 (formerly known as laminin 6) and 511
(formerly known as laminin 10), and the vascular basement membrane
contains laminins 411 (formerly laminin 8) and 511. The structure,
biologic functions and sequelae of genetic defects of laminins expressed
in the skin are discussed in more detail in Chapters 28 and 32.
Other glycoproteins with important functions in the skin are listed
in Table 95.4.
Functions of the Extracellular Matrix

Structural role of the extracellular matrix
In the past, the ECM was regarded as a structural scaffold that gave
organs their shape and consistency. Over the past decade, considerable
progress has been made in our understanding of the broad spectrum
of distinct ECM suprastructures and their specific functions1,2. For
example, corneal stroma contains stacked sheets of parallel fibrils with
a uniform and small diameter. In each consecutive layer, the fibrils are
oriented almost perpendicularly to the adjacent layers, rendering the
tissue resistant to high tensile forces in two dimensions and, at the
same time, allowing undisturbed penetration of visible light. Basement
membranes are sheets with limited tensile strength but important
tissue-specific properties that allow for particular cell attachments and
regulate morphogenesis, differentiation and barrier functions. In the
dermis, various ECM networks are embedded in the water-binding
extrafibrillar matrix, maintaining the elasticity, resilience and tautness
of the skin. At the dermalepidermal junction, specific basement
membrane-associated aggregates ensure strong adhesion of the epidermis and the dermis and, as a result, provide resistance against external
shearing forces (see Ch. 28).
Regulation of cellular functions

In addition to their structural roles, ECMs are biologically active. In
vitro studies and transgenic and knockout mouse models (see Ch. 3)
have demonstrated the importance of ECMs as potent regulators of
cellular functions during development, regeneration, wound healing,
inflammation and tumorigenesis. ECM macromolecules can influence
a multitude of cellular processes and events, such as adhesion, migration, cytoskeletal organization, determination of cell shape and polarization, division, differentiation and apoptosis.
Cells use a variety of receptors, such as integrins and cell surface
proteoglycans, to recognize signals from the ECM2. The family of 1
integrins represents the most common class of matrix receptors. The
-subunit of the integrin determines the specificity for individual
matrix protein ligands, but the affinity and degree of specificity vary.
Some integrins recognize only one ligand, while others can bind to
several matrix proteins.
Signals from the ECM can have different effects on the cell16. For
example, they can induce clustering of integrins on the cell surface and
lead to formation of protein complexes between the cytoplasmic domains
of the integrins and the cytoskeleton, thereby influencing cell shape.
Alternatively, activation of integrins by the ECM can stimulate signal
transduction pathways involving focal adhesion kinase (protein tyrosine
kinase 2), paxillin and tensin. ECMintegrin interaction may also induce
mitogen-activated protein kinase-mediated regulation of transcription,

Pro-TGF-
Cleavage*
Large
latent
complex
Small latent
complex
TGF- latency
associated peptide
TGF-
Latent TGF-
binding protein
Cutis laxa with severe

multisystem involvement
Secretion**
Intracellular
Extracellular
Elastic fibers
CHAPTER
95
Transforming growth factor beta signaling, vascular remodeling, and

hypertension. N Engl J Med. 2006;354:27213.
Protease
N
Fig. 95.7 Regulation of transforming growth

factor- (TGF-) activity. TGF- is synthesized as an
inactive homodimeric propeptide, pro-TGF-. After
cleavage, mature TGF- is sequestered in an inactive
form via its continued association (now noncovalent) with the latency-associated peptide (LAP;
forming the small latent complex) and covalent
linkage of the LAP to the latent TGF- binding
protein (LTBP; forming the large latent complex). In
addition, the large latent complex becomes attached
to the extracellular matrix (ECM) via covalent linkage
of the LTBP N-terminus with ECM proteins and
non-covalent association of the LTBP C-terminus with
fibrillin-1 (a member of the LTBP/fibrillin superfamily).
Solubilization of the large latent complex from the
ECM can occur via proteolytic cleavage of susceptible
hinge regions within the LTBP and disruption of the
fibrillin-1LTBP interaction by fibrillin-1 fragments.
Binding of ECM glycoproteins such as
thrombospondin 1 to the LAP results in the release
of active TGF- that can bind to its receptors and
promote fibrosis. Adapted from August P, Suthanthiran M.
REGULATION OF TRANSFORMING GROWTH FACTOR- (TGF-) ACTIVITY
Fibrillin 1-containing
microfibrils
Release of soluble large

latent complex
Cutis laxa
Elastin
Fibulin-4, -5
Marfan
syndrome
Angiotensin II receptor blockers
Active TGF-
Thrombospondin 1
Fibrillin 1 fragment
Fibrosis
* Both intracellular and extracellular cleavage have been reported;

cleavage can occur before or after association with LTBP
** Small latent complexes and pro-TGF- may also be secreted
cell proliferation and differentiation. A further level of regulation of

integrin-mediated ECM signaling results from the regulation of integrin
activation through divalent cations, phospholipids and other agents17.
Growth factors of the TGF- family are potent regulators of ECM
formation, in addition to their immunomodulatory functions and regulatory roles in cell growth2. They are secreted from cells as latent
complexes containing TGF- and its propeptide latency-associated
peptide (LAP). In most cells, LAP is covalevntly linked to LTBP, forming
the large latent complex (see above and Fig. 95.7). The secreted large
latent complexes associate covalently with the ECM proteins via the
N-termini of the LTBPs. TGF- can be released from the complexes by
various matrix-degrading proteinases originating from fibroblasts or
inflammatory cells. In addition to the LTBPs, several other ECM molecules can bind to TGF- and modulate its activity, such as thrombospondin and the core proteins of the proteoglycans decorin, biglycan
and fibromodulin2.
DISEASES RELATED TO ECM DEFECTS

Molecular studies of the genes and proteins involved in diseases of the
ECM have produced a wealth of information regarding the normal
biology of the ECM1821. Putative functions for many matrix macromolecules were found for the first time, or confirmed, when mutations in
their genes were shown to cause diseases. For example, functions of the
minor fibrillar collagens V, IX and XI in controlling the collagen fibril
diameter have been ultimately proven via studies of animal or human
genetic disorders3. The fundamental roles of collagens VII and XVII in
dermalepidermal adhesion became clear when mutations in the corresponding genes were discovered in patients with hereditary epidermolysis bullosa (EB)18. Genetic ECM diseases with cutaneous
manifestations are listed in Table 95.5, and the molecular mechanisms
and pathophysiology of selected conditions are delineated below. Ehlers
Danlos syndrome (EDS), cutis laxa and pseudoxanthoma elasticum
(PXE) are covered in more depth in Chapter 97, and EB is discussed in
Chapter 32.
EhlersDanlos syndrome
The quantitatively major components of the collagen fibrils found in
the ECMs of many tissues (e.g. skin, tendon, bone, cartilage) are
collagens I, II (absent from the skin) and III. Smaller amounts of
other minor collagens (e.g. types V, IX, XI, XII, XIV) are expressed
in a tissue-specific manner3. Mutations in the genes encoding major
or minor collagens can result in distinct constellations of

1591
PROTEOGLYCANS OF THE SKIN

Proteoglycan
SECTION
15
Gene
Size of the core protein (kDa)
Glycosaminoglycan (GAG) side chains (number)
Versican
CSPG2
265370, splice variants
Chondroitin/dermatan sulfate (1030)
Perlecan
HSPG2
400467
Heparan/chondroitin sulfate (3)
Decorin*
DCN
40
Fibromodulin*
RMOD
42
Keratan sulfate (23)
Lumican*
LUM
38
Keratocan*
KERA
38
Biglycan*
BGN
40
Syndecans 1, 2, 4
SDC1
SDC2
SDC4
35120
Heparan/chondroitin sulfate (35)
*Small leucine-rich proteoglycan.

Table 95.3 Proteoglycans of the skin.
GLYCOPROTEINS OF THE SKIN

Glycoproteins
Key functions
Fibronectin
Cell adhesion and migration
Vitronectin
Cell adhesion and migration
Thrombospondins (4 types)
Cell-to-cell and cell-to-matrix

communication
Matrilins (4 types)
Matrix assembly, cell adhesion
Tenascins (4 types)
Regulation of cellular function
VERSICAN STRUCTURE AND AGGREGATES

Versican core protein plus GAG side chains
A
Ig
LP
LP
GAGa
GAGb
EG EG
Lectin CR
B
Hyaluronic acid
Link protein
Table 95.4 Glycoproteins of the skin.
GAG side chain
1592
abnormalities in different organs, including several types of EDS (see

Ch. 97)19. For example, defects in the COL3A1 gene encoding collagen
III are responsible for the vascular type of EDS (type IV), an autosomal
dominant condition that presents with thin translucent skin, excessive bruising, and life-threatening arterial, gastrointestinal and uterine
ruptures. Mutations in the COL3A1 gene have also been found
in a subset of patients with arterial aneurysms as the primary clinical
manifestation.
Alterations in several genes encoding minor fibrillar collagens can
also cause severe connective tissue diseases, suggesting pivotal functions for these quantitatively minor components. The 1- and the 2chains of collagen V co-polymerize with collagens I and III and have a
role in the control of fibrillogenesis. They limit the solubility of macromolecules in the fibrils and regulate the geometry of lateral aggregation as well as the overall shapes and sizes of the collagen aggregates.
Consistent with this concept, the classic type of EDS (types I & II)
rarely results from mutations in the COL1A1 gene encoding the 1chains of collagen I, whereas mutations in the COL5A1 and COL5A2
genes encoding the 1- and 2-chains of collagen V account for approximately 50% of patients21. Patients with this form of EDS exhibit variable degrees of skin hyperelasticity and fragility, atrophic scarring and
joint hypermobility (Fig. 95.9A). Since collagen V is a heterotrimeric
molecule consisting of 1(V) and 2(V) with or without 3(V) chains,
COL5A3 is another candidate gene for EDS (although mutations in this
gene have not been identified to date). Mutations in the gene encoding
tenascin-X, a glycoprotein in the extrafibrillar matrix, can cause a recessive form of EDS with similar clinical findings of hyperextensible skin
and joint hypermobility21.
Mutations in genes that encode proteins involved in the posttranslational modification of collagen (see above and Fig. 95.2) have
been found to underlie other forms of EDS. For example, loss-offunction mutations in the lysyl hydroxylase 1 gene lead to abnormal
lysyl hydroxylation and glycosylation of collagens in patients with the
kyphoscoliosis type of EDS (type VIA), a recessive disease characterized
by hyperextensible and fragile skin as well as hypermobile joints, scoliosis and ocular fragility. Recently, mutations in the gene encoding
Versican core protein
Fig. 95.8 Versican structure and aggregates. A The core protein contains
several structural motifs important for glycosaminoglycan (GAG) and ligand
binding. The N-terminal immunoglobulin-type repeat (Ig) is followed by two
consecutive link-protein type modules (LP), which are involved in mediating
the binding of the core protein to hyaluronic acid. The GAG binding domain,
which comes in tissue-specific alternative splice variants, GAG- and/or GAG-,
carries the GAG side chains. It is followed by structural motifs, including two
epidermal growth factor-like repeats (EG), a C-type lectin domain (Lectin), and
a complement regulatory protein-like module (CR). B In the dermis, versican
can form huge aggregates with hyaluronic acid (red). The core protein (blue),
which carries a number of GAG side chains (black), is bound to hyaluronic acid
via its link-protein domain (green; LP module in the scheme in panel A). The
aggregates can bind large amounts of water, and thus provide for the tautness
of the skin. Adapted from Iozzo RV. Matrix proteoglycans: from molecular design to cellular function.
Ann Rev Biochem. 1998;67:60952.
dermatan-4-sulfotransferase 1 (required for biosynthesis of dermatan

sulfate) have been identified in patients with musculocontractural
EDS (type VIB), which presents with craniofacial abnormalities, joint
contractures and wrinkled palms together with the findings of the
kyphoscoliosis type.

GENETIC EXTRACELLULAR MATRIX DISEASES OF THE SKIN

Gene
Inheritance
Disease
Phenotypic features in the skin* and other organs
Collagen I (1- and

2-chains)
COL1A1
AD
EDS, arthrochalasia (type

VIIA)
EDS, classic (type I; rare
cause of this EDS type)
Skin hyperextensibility and fragility, joint hypermobility, congenital

hip dislocation
See below
See above
AD
COL1A2
AD
AR
EDS, arthrochalasia (type

VIIB)
EDS, cardiac valvular
Collagen III
COL3A1
AD
EDS, vascular (type IV)
Translucent, fragile skin with extensive bruising; arterial fragility,

intestinal and uterine rupture
Collagen V (1- and

2-chains)
COL5A1
COL5A2
AD
EDS, classic (type I severe;

type II milder)
Skin hyperextensibility and fragility, joint hypermobility
Collagen VI
COL6A1
COL6A2
COL6A3
AD, AR
Ullrich disease
Collagen VII
COL7A1
AD, AR
Dystrophic epidermolysis
bullosa
Skin fragility and blistering
Collagen XVII
COL17A1
AR
Junctional epidermolysis
bullosa
Fibrillin-1
FBN1
AR
AD
Marfan syndrome
Striae, characteristic body habitus, aortic dilation/dissection
Congenital stiff skin syndrome Diffusely thick and hard skin, nodules on fingers, joint contractures,
short stature, entrapment neuropathy
Elastin
ELN
AD > AR
Cutis laxa, AD > AR
Lax, redundant skin
Cardiac valve defects, otherwise similar to classic EDS (see below)
distal joint hypermobility, muscular dystrophy
Fibulin-4
FBLN4
AR
Cutis laxa, AR type I
Lax, redundant skin; emphysema and arterial anomalies
Fibulin-5
FBLN5
AR > AD
Cutis laxa, AR type I > AD
Lax, redundant skin; emphysema and arterial anomalies (AR form)
Latent TGF- binding

protein-4
LTBP4
AR
Cutis laxa with severe

pulmonary, gastrointestinal
and urinary abnormalities
Lax, redundant skin; features in name of disorder, dysmorphic facies,

joint hyperextensibility, hypotonia
TGF- receptors 1 & 2
TGFRB1
TGFRB2
AD
LoeysDietz syndrome
(types I and II)
Aortic aneurysms, arterial tortuosity, skeletal anomalies, joint

hypermobility; primarily in type II: translucent skin, easy bruising,
atrophic scarring; primarily in type I: craniofacial anomalies
Tenascin-X
TNXB
AR
Skin hyperextensibility, joint hypermobility
AD
EDS, AR due to tenascin-X

deficiency
EDS, hypermobility (type III)
ECM1
AR
Lipoid proteinosis
Hyalin deposition in the dermis and submucosal tissues, hoarse

voice, intracranial calcifications
ABCC6 transporter
ABCC6
AR
Pseudoxanthoma elasticum
(PXE)
Yellowish papules, lax skin, retinal angioid streaks, cardiovascular

disease
ATPase, Cu2+transporting,
-polypeptide
ATP7A
X-R
Occipital horn syndrome
Lax skin, tortuous arteries, joint hypermobility, occipital calcifications
Solute carrier family 2,

member 10 (a glucose
transporter)
SLC2A10
AR
Arterial tortuosity
syndrome
Lax skin, telangiectasias on the cheeks, tortuous arteries, joint

hypermobility
Solute carrier family

39, member 13 (a zinc
transporter)
SLC39A13
AR
EDS-like
spondylocheirodysplasia
Skin hyperextensibility and fragility, atrophic scarring, wrinkled

palms, joint hypermobility, growth retardation
Lysyl hydroxylase 1
PLOD1
AR
EDS, kyphoscoliosis (type

VIA)
Skin hyperextensibility and fragility, ocular fragility, joint

hypermobility, scoliosis
Lysyl hydroxylase 3
PLOD3
AR
Bone fragility with

contractures, arterial
rupture and deafness
Features in name of disorder, acral blistering, easy bruising,

dysmorphic facies, hypoplastic nails, osteopenia, cataracts, delayed
growth and development
AD
Epidermolysis bullosa
simplex-like phenotype
AR
EDS, dermatosparaxis (type

VIIC)
Sagging, doughy, fragile skin; characteristic facies
ADAMTS2
95
Variable skin hyperextensibility, joint hypermobility with recurrent

dislocations
Extracellular matrix
protein-1
ADAMTS-2
(procollagen
N-proteinase)
CHAPTER
Protein
*Elastosis perforans serpiginosa can also develop in patients with EDS and pseudoxanthoma elasticum.
A phenotype with features of both EDS and osteogenesis imperfecta has also been reported.
The phenotype of LoeysDietz syndrome can mimic Marfan syndrome (type I) or vascular EDS (type II).
Table 95.5 Genetic extracellular matrix diseases of the skin. Diseases and phenotypic features are colored based on the primary cutaneous manifestation (when
applicable) as follows: orange, hyperextensible skin (as in classic EDS); pink, extensively bruised skin (as in vascular EDS); peachtan, skin fragility with blistering
(as in epidermolysis bullosa); light blue, lax skin (as in cutis laxa); dark blue, yellowish papules lax skin (as in pseudoxanthoma elasticum). ABCC6, ATP-binding
cassette subfamily C member 6; AD, autosomal dominant; ADAM, a disintegrin and metalloproteinase; AR, autosomal recessive; EDS, EhlersDanlos syndrome; TGF,
transforming growth factor; X-R, X-linked recessive.
Continued
1593
GENETIC EXTRACELLULAR MATRIX DISEASES OF THE SKIN
SECTION
15
Protein
Gene
Inheritance
Disease
Phenotypic features in the skin* and other organs
Dermatan-4sulfotransferase 1
CHST14
AR
EDS, musculocontractural
Skin hyperextensibility and fragility, wrinkled palms, ocular

fragility, joint contractures and hypermobility, scoliosis, craniofacial
abnormalities
Galactosyltransferase-I
B4GALT7
AR
EDS, progeroid
Skin hyperextensibility, joint hypermobility, progeroid facies,

osteopenia, mental and growth retardation
Vacuolar H+-A2 subunit
ATP6V0A2
AR
Cutis laxa, AR type IIA

Wrinkly skin syndrome
Lax skin, facial dysmorphism, large fontanelles, microcephaly,

delayed development growth, strabismus, joint hypermobility
Pyrroline-5carboxylate reductase
1
PYCR1
AR
Cutis laxa, AR type IIB

De Barsy syndrome (DBS)
Lax skin, facial dysmorphism, large fontanelles, microcephaly,

delayed development and growth, joint hypermobility; corneal
opacities, cataracts & athetosis in DBS
Pyrroline-5carboxylate synthetase
ALDH18A1
AR
Mental retardation, joint

hypermobility and skin
laxity
Features in name of disorder, with or without hyperammonemia
-glutamyl carboxylase
GGCX
AR
PXE-like disorder with

multiple coagulation factor
Yellowish papules, lax skin, retinal angioid streaks, cardiovascular

disease, bleeding diathesis
Golgin,
RAB6-interacting
GORAB
AR
Gerodermia
osteodysplastica
Lax skin (primarily on dorsal hands and feet), progeroid facies with
prognathism, short stature, osteoporosis
Ras and Rab

interactor 2
RIN2
AR
Macrocephaly, alopecia,
cutis laxa and scoliosis
(MACS)
Features in name of disorder, facial dysmorphism, gingival

hypertrophy, joint hyperextensibility
Filamin A (actinbinding protein 280)
FLNA
X-D
EDS, periventricular nodular

heterotopia variant
Variable skin hyperextensibility, aortic dilation, periventricular

nodular heterotopia, joint hypermobility
*Elastosis perforans serpiginosa can also develop in patients with EDS and pseudoxanthoma elasticum.
Exists on a spectrum with adducted thumb-clubfoot syndrome, which is caused by mutations in the same gene.
Table 95.5 Genetic extracellular matrix diseases of the skin (contd). Diseases and phenotypic features are colored based on the primary cutaneous
manifestation (when applicable) as follows: orange, hyperextensible skin (as in classic EDS); light blue, lax skin (as in cutis laxa); dark blue, yellowish papules lax
skin (as in pseudoxanthoma elasticum). ALDH18A1, aldehyde dehydrogenase 18 family, member A1; AR, autosomal recessive; CHST14, carbohydrate sulfotransferase
14; EDS, EhlersDanlos syndrome; X-D, X-linked dominant.
Failure to cleave the N-propeptide from procollagen I causes the

arthrochalasia type of EDS (types VIIA & VIIB), a dominant disorder
that features severe joint hypermobility, including dislocations. The
persistence of this propeptide on collagen I molecules drastically alters
fibrillogenesis, and the fibrils that form are thin and highly irregular
in diameter. Affected individuals typically have a splice-site mutation
in the COL1A1 or COL1A2 gene that causes exon skipping and elimination of the cleavage site for ADAMTS-2 (procollagen I N-proteinase)
in the pro1(I) or pro2(I) chain21. Loss-of-function mutations in the
ADAMTS2 gene itself cause another form of EDS, the dermatosparaxis
type (type VIIC; Fig. 95.9B), in which (similar to collagen I in the
arthrochalasia type), procollagen N-propeptides persist and sterically
disturb polymerization of the collagen fibrils in the skin and other
tissues21. This recessive condition has a distinct, severe phenotype
that includes characteristic facies and sagging, fragile skin with a
doughy consistency.
Cutis laxa
1594
Cutis laxa is an uncommon ECM disease characterized by genetic

heterogeneity and clinical variability (see Ch. 97); acquired variants also
exist19. In all cases, the primary diagnostic feature is loose, hyperextensible skin with decreased resilience and elasticity, leading to an appearance of too large skin and premature aging (Fig. 95.9C). The skin
changes are often accompanied by extracutaneous manifestations,
including pulmonary emphysema, bladder diverticula and pulmonary
artery stenosis. Histologically, there is marked fragmentation or diminution of elastic fibers.
Multiple genes are involved in the pathogenesis of recessive and
dominant forms of cutis laxa (see Table 95.5), including those that
encode the elastic fiber components elastin, fibulin-4 and fibulin519,22,23. A severe developmental syndrome featuring cutis laxa and
extensive pulmonary, gastrointestinal and urinary abnormalities is
caused by mutations in the latent TGF- binding protein-4 gene
(LTBP4), demonstrating that the role of TGF- signaling in ECM
assembly is essential for proper development24.
Other inherited disorders are characterized by secondary effects on

elastic fiber deposition or degradation19. For example, elastic fibers are
calcified and fragmented secondary to decreased activity of antimineralization proteins in PXE (see below and Ch. 97), and elastic
fibers are prematurely degraded due to unregulated elastase activity in
patients with 1-antitrypsin deficiency and some forms of acquired
atrophoderma. Decreased or aberrant deposition of elastic fibers in
certain tissues is also characteristic of Marfan syndrome.
Marfan syndrome
Fibrillin-1 is the major component of microfibrils and has an important structural role in elastic fibers. The highly homologous fibrillin-2
exhibits different spatial and temporal expression during development,
and the functional relationship between the two molecules is not
fully understood. Fibrillin-1 mutations underlie Marfan syndrome,
an autosomal dominant disorder with variable connective tissue
weakness of the skin as well as skeletal, ocular and cardiovascular
systems10,19,21. The cutaneous manifestations can include striae and
elastosis perforans serpiginosa. In addition to structural disturbances
in elastic fibers and microfibrils due to mutant fibrillin, emerging
data suggest that fibrillin mutations preclude or decrease the sequestration of latent TGF- complexes (see above), thus rendering them
more prone to activation. This leads to unproductive tissue remodeling, abnormal cell behavior and loss of ECM integrity10. Mutations
in the gene encoding fibrillin-2 lead to a Marfan syndrome-like condition called congenital contractural arachnodactyly, which is characterized by skeletal abnormalities in the absence of ocular and
cardiovascular features21.
Heterozygous mutations in the genes encoding the TGF- receptors
1 and 2 underlie LoeysDietz syndrome. Type I LoeysDietz syndrome
is characterized by aortic aneurysms, generalized arterial tortuosity,
craniofacial malformations (e.g. bifid uvula, cleft palate, hypertelorism),
skeletal anomalies and joint laxity. Type II LoeysDietz syndrome has
less craniofacial involvement and also features cutaneous manifestations similar to those of the vascular type of EDS, including translucent

CHAPTER
95
Fig. 95.9 Phenotypic manifestations of genetic extracellular matrix defects. A Classic EhlersDanlos syndrome (type II) with slightly overstretchable skin results
from mutations in the collagen V genes. B Dermatosparaxis showing fragile skin with purpura and a doughy texture due to mutations in the gene for ADAMTS-2.
C Cutis laxa can be caused by mutations in several different genes, including those encoding the elastic fiber components elastin, fibulin-4 and fibulin-5. D
Junctional epidermolysis bullosa with skin blisters after minimal friction can be caused by mutations in the collagen XVII gene. B, Courtesy, Julie V Schaffer, MD. C, Courtesy,
Thomas Schwarz, MD.
skin, easy bruising and atrophic scarring20,21. The phenotypic overlap

with Marfan syndrome and vascular EDS is not surprising considering
the association between fibrillin and latent TGF- and the role of
TGF- in regulating collagen expression.
Pseudoxanthoma elasticum
PXE (see Ch. 97) is a heritable disorder characterized by cutaneous,
vascular and ocular (classically angioid streaks) involvement that results
from the accumulation of fragmented and calcified elastic fibers in the
dermis, arterial walls and Bruchs membrane, respectively. The skin
findings laxity and yellowish papules and plaques are the most
common and often the earliest manifestations of PXE.
Although PXE has traditionally been considered as a prototypic heritable ECM disorder, it is caused by mutations in the gene that encodes
the ATP-binding cassette (ABC) subfamily C member 6 (ABCC6)
transmembrane transporter, which is primarily expressed in the liver25.
Mutations in the -glutamyl carboxylase gene (GGCX) can also lead to
a PXE-like phenotype together with deficiency in vitamin K-dependent
coagulation factors. GGCX catalyzes the vitamin K-dependent
-glutamyl carboxylation that activates the matrix gla protein (MGP),
which functions as an inhibitor of pathologic mineralization, as well
as coagulation factors. Although the substrates of ABCC6 remain to
be determined, it is speculated that this transporter may export a
GGCX cofactor (e.g. a vitamin Kglutathione conjugate) from the
liver into the circulation, with loss of ABCC6 function resulting in

reduced activation of MGP and, as a consequence, connective tissue
calcification25.
EB represents a diverse group of hereditary diseases characterized by
mechanical fragility of the skin that results in cutaneous blister formation (see Ch. 32)18,26. Mutations in the collagen VII gene (COL7A1)
cause both dominant and recessive forms of dystrophic EB27. Because
collagen VII is a component of the anchoring fibrils, cleavage occurs at
the level of these fibrils in the uppermost dermis (just below the lamina
densa). Patients with severe forms of recessive dystrophic EB are nulli
zygotes harboring mutations that lead to premature termination
codons27. As a consequence, anchoring fibrils and collagen VII are
absent from the skin. Milder forms of dystrophic EB are associated with
missense mutations in one or both copies of the COL7A1 gene. When
heterozygous, such mutations often exert dominant-negative effects,
since structurally aberrant collagen VII molecules are assembled and
incorporated into the anchoring fibrils, rendering them functionally
inadequate.
Mutations in the COL17A1 gene encoding the 1(XVII) chain of collagen XVII, a homotrimeric transmembrane collagen localized to the
hemidesmosome-anchoring filament complex of basal keratinocytes7,
can cause junctional EB. This recessive EB subtype is characterized by

1595
SECTION
15
cleavage within the lamina lucida of the epidermal basement membrane. Patients with two null alleles of COL17A1 tend to have widespread blistering (generalized non-Herlitz junctional EB; Fig. 95.9D),
whereas those with two missense mutations and some preservation of
collagen XVII function exhibit milder clinical phenotypes (localized
non-Herlitz junctional EB)28.
Laminin 332 (formerly known as laminin 5) is a major structural
component of the lamina densa, where it secures epidermal adhesion
by linking 64 integrin on the cell surface to collagen VII of the
anchoring fibrils. Like defects in collagen XVII, mutations in the
genes encoding the three polypeptide chains of laminin 332 cause
junctional EB. The most severe form, Herlitz junctional EB, is often
fatal during infancy; it results from null mutations and a complete
lack of laminin 332 in the skin. Missense mutations are associated
with milder forms of the disease (e.g. generalized non-Herlitz junctional EB)28.
Other hereditary matrix diseases with skin symptoms

Muscular dystrophies (Ullrich disease [more severe], Bethlem myopathy [milder]) can be caused by mutations in the COL6A1, COL6A2
and COL6A3 genes encoding the 1(VI), 2(VI) and 3(VI) chains of
collagen VI19. This collagen forms beaded filaments/microfibrils in
several tissues, including the muscle and skin. Extramuscular manifestations a puffy consistency of the skin and joint hyperlaxity
likely reflect abnormalities of the microfibrillar networks in the dermis
and synovia.
Mutations in the extracellular matrix protein-1 gene (ECM1) cause
lipoid proteinosis, a recessive multi-organ disease characterized by the
accumulation of hyalinized material in many tissues, including the
dermis (see Ch. 48)29. ECM-1 is a 85kD glycoprotein that binds to
fibulins, perlecan and laminin 33230.
Loss-of-function mutations in both copies of the PLOD3 gene encoding lysyl hydroxylase 3, an enzyme with important roles (including
glucosyltransferase and galactosyltransferase activities) in the posttranslational modification of collagens31, have been found to underlie
a severe, multi-organ connective tissue disease which features fragile
skin that is prone to blistering as well as bruising (see Table 95.5).
PLOD3 haploinsufficiency has also been documented in a family with
a phenotype limited to skin blistering. In vitro studies have demonstrated
that even a moderate decrease in lysyl hydroxylase 3 activity has deleterious consequences for the deposition and organization of the ECM32.
Extracellular matrix components as autoantigens

Several ECM components are targeted in autoimmune diseases affecting
the kidney, cartilage and skin (Table 95.6). Autoantigens in these conditions include the 3- and 5-chains of collagen IV in Goodpasture
disease33, collagen II in relapsing polychondritis, and collagens VII and
XVII in the autoimmune blistering diseases EB acquisita and bullous
pemphigoid, respectively34. The autoantigen in p200 pemphigoid, a novel
autoimmune subepidermal blistering disease, was recently identified as
the 1-chain of laminin located at the dermalepidermal junction35.
Antibodies to fibrillin-1 have been described in patients with systemic sclerosis (especially individuals of Choctaw Native American or
Japanese descent) and morphea (especially those with linear and generalized subtypes). The mutated protein in lipoid proteinosis, ECM-1,
is the target of autoantibodies in patients with lichen sclerosus, which
also features dermal hyalinization29.
The immunodominant epitopes in autoimmune disorders are often
localized to one or several distinct structural domains and, therefore,
recombinant domains can be employed for precise diagnostic testing. It
is thought that binding of autoantibodies to ECM components disturbs
their supramolecular aggregation or ligand binding, which in turn leads
to functional deficiency and corresponding clinical symptoms.
Skin aging and other acquired ECM abnormalities
1596
Changes in the dermal ECM contribute to both chronologic and photoinduced skin aging. Morphologic hallmarks of aged skin include
reduced microfibrils in the papillary dermis, disorganized elastic fibers,
and reduction and weakening of other ECM fibril networks. Although
the molecular details of these ECM changes are not fully understood,
it is generally accepted that the structurally perturbed dermal networks
EXTRACELLULAR MATRIX COMPONENTS AS TARGETS

IN AUTOIMMUNE DISEASES
Disease(s)
Autoantigen(s)
Biologic and clinical

features
Goodpasture disease
Collagen IV, 3- and

5-chains
Glomerulonephritis,
pneumonitis with
hemoptysis
Relapsing polychondritis,
arthritis
Collagen II; collagen IX
Chondritis of ear, larynx

and trachea; arthritis
Pemphigoid (various
subtypes)
Collagen XVII (BP, PG,

MMP)*; laminin 332
(MMP); laminin-1 chain
(p200 pemphigoid)
Skin blistering
acquisita
Collagen VII
Skin blistering, fragility
Bullous eruption of
systemic lupus
erythematosus (SLE)
Collagen VII
Skin blistering with

underlying SLE
Scleroderma
Fibrillin-1; PDGF receptor
Skin fibrosis
Lichen sclerosus
Extracellular matrix
(ECM) protein-1
Inflammation, epidermal
atrophy, hyalinization of
the dermis
*Also the autoantigen in linear IgA bullous dermatosis.
Not confirmed in large patient cohorts.
Table 95.6 Extracellular matrix components as targets in autoimmune

diseases. BP, bullous pemphigoid; PDGF, platelet-derived growth factor; MMP,
mucous membrane (cicatricial) pemphigoid; PG, pemphigoid gestationis.
cannot bind adequate amounts of hyaluronic acid and, consequently,

water, which leads to lax and wrinkled skin. The biosynthetic activity
of all cells diminishes during aging, but reduced synthesis of dermal
collagens by fibroblasts is a particularly prominent feature. This has
been shown to be mediated by decreased TGF- and connective tissue
growth factor (CTGF) signaling36. Increased degradation of ECM components also occurs and destabilizes network structures. The deleterious effects of UV irradiation include release of cytokines from the
epidermis and generation of reactive oxygen species. These mediators
induce inflammatory processes and stimulate expression and activation
of a spectrum of matrix metalloproteinases and serine proteinases such
as elastase, which can degrade ECM networks37.
Weakened ECMs lead to disturbed wound healing and a bruising
tendency in scurvy, a disease resulting from an insufficient supply of
ascorbic acid (vitamin C). This vitamin is an essential cofactor for
prolyl and lysyl hydroxylases, which modify collagens during their
biosynthesis and are required for cross-linking4.
In fibrotic disorders such as scleroderma (systemic sclerosis) and
keloids, thickened skin reflects excessive ECM in the dermis. The
reasons for the accumulation are not fully understood; inflammationmediated upregulation of ECM synthesis (e.g. collagen, fibrillins, proteoglycans) via TGF- and CTGF are believed be causative mechanisms
in scleroderma (see Ch. 43). A keloid is an overgrowth of dense fibrous
tissue in the skin as a result of trauma. The cellularity of keloids is
increased, and the ECM shows abnormal thin fibrils that are haphazardly organized in dense nodules. Various abnormalities of ECM biosynthesis have been measured in keloid fibroblasts in vitro, and matrix
assembly is perturbed38. Gene profiling studies indicated a role for multiple fibrosis-related pathways in the pathogenesis of keloids39, but the
regulatory mechanisms leading to excessive ECM accumulation still
remain unclear. A genetic predisposition for keloid formation seems to
exist. Among Caucasians, 510% of individuals with keloids have a
positive family history; among Africans, the prevalence is much higher.
Animal Models
Mouse models for ECM diseases have produced new insights into
pathomechanisms, allowed further assessment of abnormalities
observed in human diseases, and enabled testing of novel therapeutic
approaches40. For example, mice with a targeted mutation in one

Potential for Biologically Valid

Molecular Therapies
Clarification of the molecular mechanisms underlying ECM disorders
forms a basis for novel therapeutic approaches. Diseases well suited
for such therapies include recessive forms of EB caused by a lack
of collagen VII, collagen XVII or laminin 332. Currently, preclinical

and clinical pilot trials on gene-, cell- and protein-based therapies
are ongoing for recessive dystrophic and junctional EB (reviewed in
refs 44 & 45).
Gene therapy with delivery of gene-corrected stem cells or vectors
directing the expression of the missing protein has the advantage of
continuous protein biosynthesis in the skin but may carry a risk of
oncogenesis. Retroviruses, lentiviruses and non-viral transposonmediated gene transfer have been successfully used to restore collagen
VII or laminin 332 synthesis in keratinocytes in vitro. In the first
human pilot study on EB, laminin-3-deficient skin of an adult patient
was corrected by transplantation of stem cell-enriched epidermal grafts
transduced ex vivo with a retroviral vector expressing normal LAMB3
cDNA. The treatment resulted in sustained synthesis and proper
assembly of functional laminin 332 and, clinically, an absence of blistering in the corrected epidermis.
For recessive dystrophic EB, cell- and protein-based therapies
have also shown promise. Murine and human studies have demonstrated that intradermal injection of allogeneic fibroblasts leads
to increased deposition of collagen VII at the dermalepidermal
junction and clinical improvement for several months. Intriguingly,
a systemic approach using bone marrow transplantation after total
or partial myeloablation has resulted in substantial proportions of
donor cells in the skin, increased collagen VII deposition at the
dermalepidermal junction and variably decreased blistering in children with recessive dystrophic EB. Protein therapy with intradermal
injection of recombinant human collagen VII (which has a long
half-life) has been shown to result in correct protein deposition
within anchoring fibrils and reduced blistering in mouse models
of dystrophic EB.
For the treatment of dominant disorders, strategies to silence expression of the mutated allele (preventing dominant-negative effects) or to
supplement with normal protein (correcting haploinsufficiency) hold
promise46.
Better understanding of molecular and cellular disease mechanisms disclosed an unexpected pharmacologic approach to the
treatment of Marfan syndrome47. Since excessive TGF- signaling
contributes to the development of aortic aneurysms in individuals with this condition, it was hypothesized that TGF- antagonists might prevent or partially reverse this disease manifestation.
Indeed, angiotensin II receptor blockers are now successfully
employed to prevent aortic root dilation in patients with Marfan
syndrome48.
Future development of successful therapies for connective tissue
disorders will also depend on the progress in our understanding
of alloy formation by matrix macromolecules. This endeavor will
be facilitated not only by the analysis of aggregate formation by
matrix macromolecules or their mixtures in vitro, but also by the
elucidation of further genetic defects and their consequences in
animal or human diseases, as well as the generation of transgenic
animals as models for human disorders. This combined information will help us to understand and treat not only inherited ECM
diseases but also many common disorders currently considered as
acquired.
CHAPTER
95
collagen V gene were noted to have thin, fragile skin with disorganized
and loosely packed fibrils, which pointed to collagen V genes as candidates for EDS prior to the detection of human mutations. Likewise, a
tenascin-X-deficient mouse reproduced the symptoms of human recessive EDS, i.e. greatly disturbed biomechanical properties of the skin but
milder joint abnormalities.
For fibrillin-1, transgenic mouse models have been used to discern
genotypephenotype correlations. Analyses of different models revealed
an association between fibrillin-1, microfibril assembly and TGF-
signaling, showing that a defect in the latter is central to Marfan syndrome pathogenesis and phenotypic variability9,10.
Targeted ablation of the elastin gene in mice leads to fatal obstructive
arterial disease characterized by subendothelial cell proliferation and
reorganization of smooth muscle, suggesting that elastin has a role in
regulating cellular proliferation8. The phenotype of heterozygous mice
suggested that human supravalvular aortic stenosis may be caused by
functional hemizygosity of the elastin gene, which was confirmed by
mutational analysis in humans. Of note, while loss-of-function elastin
mutations that lead to haploinsufficiency are associated with supravalvular aortic stenosis, cutis laxa can result from dominant-negative
missense mutations in the elastin gene.
Collagen VII-deficient mice recapitulate the clinical, genetic, immuno
histochemical and ultrastructural characteristics of recessive dystrophic
EB in humans19. Collagen VII knockout mice die during the first 2
weeks of life, while mice with hypomorphic mutations have a severe
phenotype but live into adulthood41. These mice have provided significant information regarding the molecular pathogenesis of recessive
dystrophic EB, and they have become useful for testing cellular and
molecular approaches to therapy42. Mice lacking collagen XVII exhibit
a moderately severe form of junctional EB43 and are also being used to
study novel therapeutic approaches.
Mice harboring disrupted proteoglycan genes have demonstrated the
importance of these molecules for cutaneous tautness and integrity11.
The decorin knockout mouse has fragile skin with markedly reduced
tensile strength, associated with coarser, irregular ECM fibers in the skin
and tendons; these findings established the fundamental role for decorin
in regulating collagen fibrillogenesis in vivo. Mice with a disrupted syndecan 4 gene have a significant wound-healing defect and impaired
angiogenesis within granulation tissue, suggesting that this cell surface
proteoglycan has an important role in wound healing and angiogenesis.
Abnormalities in collagen-processing enzymes also occur spontaneously in animals. Bovine dermatosparaxis is a recessively inherited
connective tissue disorder that, like the human form of this disease,
features extreme fragility and droopiness of the skin as well as joint
laxity. Both human and bovine dermatosparaxis result from mutations
in the gene encoding ADAMTS-2, which excises the N-propeptide of
procollagens I and II19.
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ATROPHIES AND DISORDERS OF DERMAL CONNECTIVE TISSUES SECTION 15

Our knowledge of ECM macromolecules has expanded dramatically

Biology of the Extracellular Matrix

STRUCTURE AND FUNCTION OF THE

Collagen triple helix

Descargado de ClinicalKey.es desde Universidad Autonoma de Bucaramanga julio 16, 2016.

COMPONENTS OF THE EXTRACELLULAR MATRIX

Atrophies and Disorders of Dermal Connective Tissues

BIOSYNTHESIS OF A PROTOTYPE COLLAGEN

Collagens (28 types)

**15 of which are well characterized.

Table 95.1 Components of the extracellular matrix (ECM). These belong to

DERMAL EXTRACELLULAR MATRIX NETWORKS

Fig. 95.1 Dermal extracellular matrix networks. Different molecules

glycosylation of some of the Hyl residues to galactosyl-Hyl and

Fig. 95.2 Biosynthesis of a prototype collagen. The procollagen -chains

in humans, flies and worms. Trends Genet. 2004;20:3343.

residues to Hyp, and lysyl hydroxylases, which hydroxylate Lys residues

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1(V), 2(V), 3(V)

1(XI), 2(XI), 3(XI)

Skin, most ECM

Table 95.2 The collagen family of proteins. The

With collagen II heterotypic fibrils

1(IX), 2(IX), 3(IX)

With collagen II heterotypic fibrils

THE COLLAGEN FAMILY OF PROTEINS

BASEMENT MEMBRANE COLLAGENS

1(IV), 2(IV), 3(IV),

All basement membranes, isoforms vary

1(VI), 2(VI), 3(VI)

Skin, other microfibril-containing tissues

Skin, subendothelial matrices

ANCHORING FIBRIL COLLAGEN

Skin, mucous membranes, cornea

Skin, many tissues

Many tissues; parent molecule of restin

Schwann cells; fetal skin and calvaria

*Classification based upon cDNA sequence.

chains4. The extracellular processing enzymes have a higher substrate

Collagen VII-containing anchoring fibrils in the upper dermis appear

The collagen family of proteins

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-chains, which form three major networks: (1) 1/2-containing; (2)

Collagens of the skin

Atrophies and Disorders of Dermal Connective Tissues

SUPRAMOLECULAR ASSEMBLIES OF COLLAGENS

Triple helical region

Fig. 95.3 Supramolecular assemblies of collagens.

4. Collagen VI forming beaded filaments

5. Collagens forming hexagonal

6. Anchoring fibril collagen VII

8. Multiplexin collagens XV and XVIII

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are associated with abnormalities of skin collagens or the enzymes that

keratinocytes also express a second transmembrane collagen, type XIII,

ELASTIC FIBER ASSEMBLY

Fig. 95.5 Elastic fiber assembly. This model is based

Descargado de ClinicalKey.es desde Universidad Autonoma de Bucaramanga julio 16, 2016.

Fig. 95.6 Microfibrils in

Atrophies and Disorders of Dermal Connective Tissues

(see below; Fig. 95.7). The LTBP-1/latent TGF- complex (referred to

The Extrafibrillar Matrix