1 School of Medicine, University of Manchester, Manchester M13 9PT, UK
2 School of Biological Sciences, University of Manchester, Manchester M13 9PT,
UK
* Author for correspondence (e-mail: cay.kielty{at}man.ac.uk )
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Summary |
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Key words: Elastic fibres, Microfibrils, Elastin, Fibrillin, MAGP, Fibulin
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Introduction |
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Genesis of elastic fibres in early development involves deposition of
tropoelastin (the soluble precursor of mature elastin) on a preformed template
of fibrillin-rich microfibrils (Figs
1,
2)
(Mecham and Davis, 1994).
Mature elastic fibres are thus a composite biomaterial comprising an outer
microfibrillar mantle and an inner core of amorphous crosslinked elastin.
Fibrillins and fibrillin-rich microfibrils are conserved in medusa jellyfish
(Reber-Muller et al., 1995
),
invertebrates (Thurmond and Trotter,
1996
) and vertebrates (Pereira
et al., 1993
; Zhang et al.,
1994
; Nagase et al.,
2001
). Tropoelastin evolved more recently to reinforce the high
pressure closed circulatory systems of higher vertebrates
(Faury, 2001
). The
distribution of microfibrils in dynamic elastic tissues such as blood vessels,
lung, ligaments and skin implies a central biomechanical role. Microfibrils
are also abundant in some flexible tissues that do not express elastin [e.g.
the ciliary zonules that hold the lens in dynamic suspension
(Ashworth et al., 2000
)], which
emphasises their independent evolutionary function.
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Elastic fibres are designed to maintain elastic function for a lifetime.
However, various enzymes (matrix metalloproteinases and serine proteases) are
able to cleave elastic fibre molecules
(Kielty et al., 1994;
Ashworth et al., 1999c
).
Indeed, loss of elasticity due to degradative changes is a major contributing
factor in ageing of connective tissues, in the development of aortic aneurysms
and lung emphysema, and in degenerative changes in sun-damaged skin
(Watson et al., 1999
). The
importance of elastic fibres is further highlighted by the severe heritable
connective tissue diseases caused by mutations in components of elastic fibres
(for reviews, see Robinson and Godfrey,
2000
; Milewicz et al.,
2000
). Fibrillin-1 mutations cause Marfan syndrome, which is
associated with cardiovascular, ocular (ectopia lentis) and skeletal defects;
fibrillin-2 mutations cause congenital contractural arachnodactyly (CCA) with
overlapping skeletal and ocular symptoms; and elastin mutations cause Williams
syndrome, supravalvular stenosis (SVAS) and cutis laxa
(Tassabehji et al., 1998
).
Recently, pseudoxanthoma elasticum (PXE), a heritable disease associated with
elastic fibre calcification was linked to an ion channel protein
(Le Saux et al., 2001
;
Ringpfeil et al., 2001
).
The biology of elastic fibres is complex because of their multiple components, tightly regulated developmental pattern of deposition, multi-step hierarchical assembly, unique elastomeric properties and influence on cell phenotype. Below we discuss how the molecular complexity of the elastic fibre system is being unravelled by progress in identifying interactions between microfibrillar molecules and tropoelastin, detailed ultrastructural analyses and studies of mouse models.
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Elastic fibre organisation |
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These findings allowed us to develop a model of fibrillin alignment in
extensible microfibrils in which intramolecular folding would act as a
molecular `engine' driving extension and recoil
(Baldock et al., 2001;
Kielty et al., 2002
). The
model predicts that maturation from initial parallel head-to-tail alignment
(
160 nm) to an approximately one-third stagger (
100 nm) occurs by
folding at the termini and the proline-rich region, which would align known
fibrillin-1 transglutaminase crosslink sequences. Microfibril elasticity (in
the range 56-100 nm) would require further intramolecular folding at flexible
sites, which could be links between 8-cysteine motifs (also called `TB'
modules because of homology to TGFß-binding modules in latent
TGFß-binding proteins) and calcium-binding epidermal-growth-factor-like
(cbEGF) domains.
In tissues, microfibrils form loosely packed parallel bundles. X-ray fibre
diffraction of hydrated zonular microfibril bundles has identified
one-third-staggered `junctions' that could modulate force transmission, and
quick-freeze deep-etch analysis of zonules has detected links between
microfibrils (R. P. Mecham, personal communication). X-ray studies and
mechanical testing of microfibril bundles showed that bound calcium influences
load deformation but is not necessary for high extensibility and elasticity
(Wess et al., 1997;
Wess et al., 1998a
;
Wess et al., 1998b
;
Eriksen et al., 2001
). Thus,
microfibril elasticity is modified by, but not dependent on calcium-induced
beaded periodic changes, which is consistent with the molecular folding
model.
Elastic fibres
Ultrastructural analysis has shown that the elastic fibre core is not
really amorphous but instead laterally packed, thin ordered filaments
(Pasquali-Ronchetti and Baccarani-Contri,
1997). The architecture of mature elastic fibres is intricate and
highly tissue specific, reflecting specific functions in different tissues. In
the medial layer of the aorta and elastic arteries, elastic fibres form
concentric fenestrated lamellae separated by smooth muscle cell (SMC) layers;
this arrangement imparts elasticity and resilience to blood vessel walls. In
lung, elastic fibres are present in blood vessel walls and as thin highly
branched elastic fibres throughout the respiratory tree that support alveolar
expansion and recoil during breathing. The reticular dermis of skin contains
thick, horizontally arranged elastic fibres, whereas the papillary dermis
contains thinner perpendicular elastic fibres (elaunin fibres) that merge with
the microfibrillar cascade (oxytalan fibres) that intercalates into the
dermal-epidermal junction. This continuous elastic network imparts elasticity
throughout skin from the reticular and papillary dermis to the epidermis. In
auricular cartilage, a thin network of elastic fibres interspersed with
collagen fibrils in the interterritorial zone contributes to tissue
deformability. Elastic fibres are abundant in flexible ligaments, but sparse
in tendons. Tissue-specific arrangements are dictated by the mesenchymal cells
that deposit and orientate the microfibril template, and by functional
demands.
The biomechanical limitations in microfibrils that led to the evolution of elastin and the appearance of elastic fibres should be revealed once microfibril elastic properties are better understood. Thus, the molecular folding elastic `motor' model needs rigorous assessment, and both flexible sites within fibrillin-1 and crosslinks that modulate force transmission within and between microfibrils must be identified and characterised. Although it has been recognised for many years that microfibrils form a template for elastin, precisely why microfibrils have this role is still a central question in elastic fibre biology. It is also not clear whether elastin-associated microfibrils differ from those that do not associate with elastin. New insights into the cellular and extracellular basis of tissue-specific elastic fibre architecture are also needed.
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Molecular complexity |
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Microfibrillar molecules
Fibrillins are the principal structural components of
elastic-fibre-associated microfibrils. Fibrillin-1 and fibrillin-2 are encoded
by genes on chromosomes 15 and 5, respectively
(Pereira et al., 1993;
Zhang et al., 1994
), and a
third, closely related, fibrillin-3 gene has been identified on chromosome 19
(Nagase et al., 2001
). The
molecules are large glycoproteins (
350 kDa) whose primary structures are
dominated by cbEGF domains that, in the presence of Ca2+, adopt a
rodlike structure (Downing et al.,
1996
). Fibrillin-1 and fibrillin-2 have distinct but overlapping
patterns of expression (Zhang et al.,
1995
). Fibrillin-2 is generally expressed earlier in development
than fibrillin-1 and may be particularly important in elastic fibre formation
(Pereira et al., 1997
).
Fibrillin-3 was isolated from brain, and whether it is involved in elastic
fibres is unknown (Nagase et al.,
2001
).
Apart from the fibrillins, microfibril-associated glycoprotein 1 (MAGP-1)
(sometimes known as MFAP-2) is possibly the best candidate for an integral
microfibril molecule important for structural integrity
(Gibson et al., 1989;
Trask et al., 2000a
). It is
associated with virtually all microfibrils and widely expressed in mesenchymal
and connective tissue cells throughout development. Human MAGP-1 is a 183
residue molecule that has two distinctive domains: an acidic N-terminal half
that is enriched in proline residues and has a clustering of glutamine
residues, and a C-terminal portion that contains 13 cysteine residues and has
a net positive charge. MAGP-1 localises to microfibril beads (sometimes two
per bead) (Henderson et al.,
1996
; Kielty and Shuttleworth,
1997
) and is probably disulphide bonded to microfibrils since
reduction is required for its extraction.
MAGP-2, the other member of this small microfibrillar protein family, is a
170-173 residue protein structurally related to MAGP-1 mainly in a central
region (Gibson et al., 1998;
Segade et al., 2002
). MAGP-2
is rich in serine and threonine residues and contains an RGD cell-recognition
motif through which it binds to the
vß3 integrin
(Gibson et al., 1999
). MAGP-2
localises to elastin-associated and elastin-free microfibrils in a number of
tissues (Gibson et al., 1998
).
However, its restricted patterns of tissue localisation and developmental
expression suggest that MAGP-2 has a function related to cell signalling
during microfibril assembly and elastinogenesis.
The latent TGFß-binding proteins (LTBPs) are members of the fibrillin
superfamily as a consequence of domain homology. LTBPs are smaller molecules
than fibrillins but also comprise repeating cbEGF domains interspersed with TB
modules, the latter being found only in the fibrillin superfamily
(Sinha et al., 1998;
Oklu and Hesketh, 2000
).
Specific TB modules in LTBP1, LTBP3 and LTBP4 can bind to TGFß
intracellularly, forming a large latent complex that is secreted and then
crosslinked to the ECM by transglutaminase. Subsequent proteolytic release of
the LTBP-TGFß complex from ECM precedes TGFß activation. Thus, LTBPs
play an important role in tissue targeting of TGFß. LTBP-1 colocalises
with microfibrils in skin and cell layers of cultured osteoblasts and in
embryonic long bone but not cartilage
(Taipale et al., 1996
;
Raghunath et al., 1998
;
Dallas et al., 2000
). Thus,
LTBP-1 is unlikely to be an integral structural component, but its association
implicates microfibrils in TGFß targeting (see below). LTBP-2 colocalises
with fibrillin-rich microfibrils in elastic-fibre-rich tissues especially in
the response to arterial injury, and in trabecular bone
(Gibson et al., 1995
;
Sinha et al., 2002
;
Kitahama et al., 2000
). It is
a good candidate for an integral microfibrillar molecule, although it does not
bind to TGFß. It will be of interest to establish whether LTBP-3 and
LTBP-4 (Yin et al., 1995
;
Giltay et al., 1997
;
Saharinen et al., 1998
), both
of which can bind TGFß, can interact with microfibrils and elastic
fibres.
Several other microfibril-associated proteins have been identified
immunohistochemically, but little is known about whether they are essential
microfibrillar components and how they might influence microfibril function.
Microfibril-associated protein (MFAP)-1 (also known as AMP), MFAP-3 and MFAP-4
(also known as MAGP-36) colocalise with elastic fibres in skin and other
tissues (Horrigan et al.,
1992; Abrams et al.,
1995
; Liu et al.,
1997
; Lausen et al.,
1999
; Toyashima et al.,
1999
; Hirano et al.,
2002
). In ageing and immune conditions, microfibrils can associate
with amyloid deposits and accumulate a coating of adhesive glycoproteins such
as vitronectin (Dählback et al.,
1990
).
Several proteoglycans (PGs) also engage in critically important
interactions with microfibrils and contribute to their integration into the
surrounding ECM. Early electron microscopy observations using polycationic
dyes showed an association between PGs and elastic fibres
(Baccarani-Contri et al.,
1990). Two members of the small leucine-rich PG family, decorin
and biglycan (PG I and PG II) were detected within elastic fibres in dermis;
biglycan mapped to the elastin core and decorin mapped to microfibrils. More
recent ultrastructural approaches have shown that chondroitin sulphate
proteoglycans (CSPGs) are associated with microfibril beads, and a small CSPG
co-immunoprecipitates with fibrillin from cultured smooth muscle cell medium
(Kielty et al., 1996
).
Versican, a large CSPG of the lectican PG family, was immunolocalised to
microfibrils in skin (Zimmermann et al.,
1994
). Small CSPGs may contribute to the beaded organisation of
microfibrils, and versican may influence microfibril integration into the
surrounding ECM.
Elastic fibre interface molecules
Several molecules localise to the elastin-microfibril interface or to the
cell-surfaceelastic-fibre interface. These molecules could regulate
tropoelastin deposition on microfibrils and link elastic fibres to cell
surfaces. One such protein is emilin, a 136 kDa glycoprotein, that localises
to the elastin microfibril interface
(Bressan et al., 1993;
Doliana et al., 1999
). Four
family members have now been identified: emilin-1, emilin-2, emilin-3 and
multimerin (also known as emilin-4), all of which possess a long coiled-coil
central region (Colombatti et al.,
2000
; Doliana et al.,
2001
). Emilin-1 and emilin-2 contain short triple-helical domains
and trimerising C-terminal sequences similar to C1q and the NC1 domains of
collagen VIII and collagen X. Apart from emilin-1, it remains to be determined
which members of this family bind elastic fibres. Collagen VIII, a product of
vascular smooth muscle cells and endothelial cells and a component of their
pericellular basement membranes, localises to vascular elastic fibres and may
link them to vascular cells (Sadawa and
Konomi, 1991
).
Members of the fibulin family of cbEGF-domain molecules are also present at
elastic fibre interfaces. Three family members are strongly implicated in
elastic fibre biology: fibulin-1, fibulin-2 and fibulin-5. Fibulin-1 is
located within the amorphous core of elastic fibres but not in fibrillin-rich
microfibrils (Kostka et al.,
2001). Fibulin-5 localises to the elastin-microfibril interface
(Nakamura et al., 2002
;
Yanagisawa et al., 2002
).
Fibulin-2 localises preferentially at the interface between microfibrils and
the elastin core. It colocalises with fibrillin-1 in skin (except adjacent to
the dermal-epithelial junction), perichondrium, elastic intima of blood
vessels and the kidney glomerulus, although it does not appear to be present
in ciliary zonules, tendon, and surrounding lung alveoli and kidney tubules
(Reinhardt et al., 1996b
;
Utani et al., 1997
;
Raghunath et al., 1999b
;
Tsuda et al., 2001
).
Fibulin-2 is probably not needed for microfibril biomechanical integrity,
since labelling is not linearly periodic, and it is absent from tissues
subject to strong tensional forces (e.g. tendon, ciliary zonule). It is
strongly expressed by smooth muscle cells during cardiovascular development
and may be important in elastic fibre deposition and cell migration
(Tsuda et al., 2001
).
MP78/70 (also known as ß-ig-h3 or keratoepithelin) is another molecule
that occasionally appears at elastic fibre interfaces. Originally identified
in bovine tissue extracts designed to solubilise microfibrils
(Gibson et al., 1989), it
localises to collagen fibres in ligament, aorta, lung and mature cornea, to
reticular fibres in foetal spleen, and to capsule and tubule basement
membranes in kidney (Gibson et al.,
1997
; Schorderet et al.,
2000
). No general localisation to elastic fibres was observed, but
staining in most tissues closely resembles type VI collagen (see
Table 1). In some elastic
tissues, MP78/70 is present at the interface between collagen fibres and
adjacent elastic fibre microfibrils, which suggests that it has a bridging
function.
Molecules associated with forming elastic fibres
Tropoelastin is synthesised as a soluble precursor that has a molecular
mass of 70 kDa and alternating hydrophobic and crosslinking domains
(Mecham and Davis, 1994
;
Brown-Augsberger et al.,
1995
). Interactions between hydrophobic domains are important in
assembly and essential for elasticity
(Bellingham et al., 2001
;
Toonkool et al., 2001
). The
formation of covalent lysyl-derived desmosine crosslinks by lysyl oxidase
(Csiszar, 2001
) stabilises the
polymerised insoluble product (elastin). Five lysyl-oxidase-like proteins have
now been characterised [LOX, LOXL, LOXL2 (or WS9-14), LOXL3 and LOXC]. All
share homology in their catalytic C-terminal region, but the existence of
distinct N-termini suggests different functions. Only LOX and LOXL have so far
been shown, after processing from pro-forms by bone morphogenetic protein 1
(BMP-1), to crosslink insoluble elastin
(Borel et al., 2001
).
Significant progress has thus been made in identifying molecular components of the elastic fibre system, and the challenge now is to determine their biological roles. Of the long list of microfibril-associated molecules, it is highly unlikely that all are involved in assembly. Fibrillins form the backbone of microfibrils, but more sophisticated assembly assays are needed if we are to determine whether co-localising molecules are fundamental structural elements or associated components. In few cases (e.g. MAGP-1, versican) has a direct link been made between co-immunolocalisation with fibrillin and localisation on or within beaded microfibrils, and no molecules other than fibrillins have yet been shown to be necessary for microfibril assembly. New analytical approaches are needed to define microfibril composition in different tissues and to clarify the roles in elastin deposition of molecules at microfibril interfaces with elastin and cells. Much work will then be required to establish how these molecules modulate microfibril function and elastic fibre formation.
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Molecular interactions |
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Interactions between microfibrillar molecules
Expression of deletion constructs in a mammalian system has identified an
MAGP-1 matrix-binding domain (MBD) that targets this molecule to the ECM
(Segade et al., 2002).
Although MAGP-2 contains a sequence similar to the MBD of MAGP-1, it does not
associate with the ECM, because of an amino acid residue change. Refolded
MAGP-1 produced in a bacterial system can bind to the fibrillin-1 N-terminus
(within exons 1-10) in a calcium-dependent manner
(Jensen et al., 2001
). MAGP-1
and fibrillin-1 are both substrates for transglutaminase and, although only
homotypic fibrillin-1 crosslinks have been identified to date, MAGP-1 might be
crosslinked within microfibrils
(Brown-Augsberger et al.,
1996
; Qian and Glanville,
1997
). MAGP-1 also interacts with collagen VI
(Finnis and Gibson, 1997
)
(Table 1).
A recent study showed that both MAGP-1 and fibrillin-1 interact with
decorin, a sulphated CSPG (Trask et al.,
2000a). The fibrillin-1-interacting sequence is within or adjacent
to the proline-rich region, and the interaction is with the decorin core
protein. Decorin can interact with both fibrillin-1 and MAGP-1 individually,
and together they form a ternary complex. Fibrillin-2 appears not to interact
with MAGP-1 or decorin. Its inability to interact with MAGP-1 suggests either
that fibrillin-2 does not support tropoelastin deposition or that MAGP-1 is
not necessary for this process (see below). In a separate study, decorin and
biglycan were shown not to bind to MAGP-1 and MAGP-2 in solid-phase assays,
although MAGP-1 in solution interacted with biglycan but not with decorin
(Reinboth et al., 2001
). In
these two studies, MAGP-1 was expressed in mammalian or bacterial systems,
which could explain seemingly contradictory decorin-MAGP-1 interaction
results.
The versican C-terminal lectin domain binds N-terminal fibrillin-1
sequences (Isogai et al.,
2002). However, its non-periodic association with microfibrils
indicates that versican is probably not an integral structural component.
Instead, it may associate with microfibrils, and its negatively charged
chondroitin sulphate chains may influence integration of microfibrils into the
surrounding ECM.
Microfibrillar interactions with tropoelastin
MAGP-1 binds to tropoelastin as well as microfibrillar molecules and might
be a critical elastic-fibre-linking molecule
(Brown-Augsberger et al.,
1996). The tropoelastin-binding site in MAGP-1 is a tyrosine-rich
sequence within its positively charged N-terminal half, which may interact
with a negatively charged pocket near the tropoelastin C-terminus. MAGP-1 may
interact first with fibrillin-1 and decorin during microfibril assembly and
then with tropoelastin during elastic fibre formation on the microfibrillar
template. Sequences in fibrillin-1 and fibrillin-2 (within exons 10-16)
interact with tropoelastin but only in solid-phase studies, which suggests
that exposure of a cryptic site is needed
(Trask et al., 2000b
).
Both decorin and biglycan can bind to tropoelastin. Biglycan binds more
avidly than decorin, and the biglycan core protein binds more strongly than
the intact PG (Reinboth et al.,
2001). The ability of biglycan to form a ternary complex with
tropoelastin and MAGP-1 suggests that it has a role in the elastinogenesis
phase of elastic fibre formation.
Fibulin-1 does not bind to fibrillin-1 but binds tropoelastin with low
affinity (Sasaki et al.,
1999). Fibulin-2 is not crosslinked within microfibrils but
strongly binds a fibrillin-1 N-terminal sequence (within residues 45-450;
exons 2-10) in a calcium-dependent interaction
(Reinhardt et al., 1996b
).
This sequence is also reported to contain an MAGP-1 binding site (see above).
Competition by two molecules for the same fibrillin-1-binding site could
represent an important mechanism for regulating microfibril function.
Fibulin-2 has a particularly high affinity for tropoelastin and also binds to
basement membrane molecules. Fibulin-1 and fibulin-2 interact with the
versican C-terminal lectin domain, and fibulin-2 also binds to aggrecan and
brevican (Olin et al., 2000
).
Fibulin-5 is a critical determinant of elastic fibre formation (see below). It
binds strongly to tropoelastin in a calcium-dependent manner, but not to
fibrillin-1, and colocalises with tropoelastin
(Nakamura et al., 2002
;
Yanagisawa et al., 2002
). It
serves as a ligand for cell surface integrins
vß3,
vß5
and
9ß1 through its N-terminal domain and might thus anchor
elastic fibres to cells.
Current issues
A bewildering jigsaw of molecular interactions involving fibrillin, elastin
and various microfibril-associated molecules has begun to emerge from in vitro
binding studies, and it will be a major challenge to define the temporal
hierarchy of interactions that drive microfibril and elastic fibre assembly in
vivo. The extracellular appearance of fibrillin and assembled microfibrils
precedes elastin deposition, and so the timeframe of secretion may provide
clues to roles for associated molecules in microfibril assembly or elastin
deposition. Comparisons between invertebrate microfibrils and vertebrate
microfibril-elastin composites could help identify molecules required for
elastin deposition. Cellular and in vitro assembly assays are needed to
unravel the significance in assembly of homotypic fibrillin interactions and
complexes of fibrillin-1, MAGP-1, decorin, biglycan and tropoelastin. Use of
purified assembled microfibrils as ligands may be a useful approach to
investigate interactions with associated molecules.
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Assembly |
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Fibrillin-rich microfibrils
Microfibril assembly is, in part, a cell-regulated process that proceeds
independently of tropoelastin. Fibrillin-1 may undergo limited initial
assembly in the secretory pathway (Ashworth
et al., 1999a; Trask et al.,
1999
), and in this respect is similar to other major ECM
macromolecules such as collagens, laminins and proteoglycans. Using an in
vitro transcription/translation system supplemented with semi-permeabilised
cells as the source of secretory organelles, interactions were detected
between recombinant fibrillin peptides and chaperones that play key roles in
molecular folding and N-glycosylation
(Ashworth et al., 1999b
). Such
associations may influence intracellular fibrillin assembly. Fibrillins have
N- and C-terminal cleavage sites for furin convertase; extracellular
deposition requires removal of the C-terminus
(Raghunath et al., 1999a
;
Ritty et al., 1999
), a process
influenced by N-glycosylation and calreticulin
(Ashworth et al., 1999b
).
Microfibrils assemble close to the cell surface in a process that might
require receptors, as shown for fibronectin, in which dimer interactions with
5ß1 integrins induce a conformation change that leads to linear
assembly (Sechler et al.,
2001
). Since RGD sequences in the fourth TB module of fibrillins
interact with several integrins (Sakamoto
et al., 1996
), the latter might influence microfibril assembly in
a similar manner. Tiedemann et al. have proposed that heparan sulphate
proteoglycans (HSPGs), possibly in the form of cell surface HSPG receptors,
have a role in assembly (Tiedemann et al.,
2001
). CSPGs may be needed for beaded microfibril formation (see
above). Sulphation is needed for microfibril assembly, since chlorate
treatment ablates microfibril and elastic fibre formation
(Robb et al., 1999
). This
effect may reflect the absence of a PG or undersulphation of fibrillins or
MAGP-1.
Different extracellular microfibril populations have been identified. The
extracellular environment might thus play a major role in regulating
microfibril fate. In human dermal fibroblast cultures, monoclonal antibody
11C1.3 (which binds to beaded microfibrils) does not detect microfibrils until
2 weeks in culture, but a polyclonal antibody (PF2) to a fibrillin-1 pepsin
fragment can detect abundant microfibrils within 3 days
(Baldock et al., 2001). The
time-dependent appearance of 11C1.3-reactive microfibrils suggests a form of
maturation that might be due to conformational changes, transglutaminase
crosslinking (Fig. 2) or
unmasking of a cryptic epitope. In developing vascular tissues, 11C1.3 detects
microfibrils associated with medial elastic fibres, but another monoclonal
antibody, 12A5.18, which also binds to beaded microfibrils, recognises
microfibrils only in collagen-fibril-rich tissues (S. Kogake, S. M. Hall,
C.M.K. and S. G. Haworth, unpublished). Different microfibril-associated
molecules may influence epitope availability and commit microfibrils to
distinct extracellular fates.
Elastin and fibrillin self-assembly
Under appropriate in vitro conditions of temperature and ionic strength,
elastin undergoes a process of ordered self-aggregation called coascervation
caused by multiple and specific interactions of individual hydrophobic
domains, which are usually induced by an increase in temperature
(Bellingham et al., 2001;
Toonkool et al., 2001
). The
elastin aggregates formed through coascervation appear as ordered fibrillar
structures resembling the elastic fibre core, indicating that the protein has
an intrinsic ability to organise into polymeric structures. In vivo,
tropoelastin probably binds microfibrils, and then coascervates and becomes
crosslinked by lysyl oxidase (Fig.
2).
The molecular form of fibrillin secreted from cells is controversial. As in the case of most major ECM polymers, fibrillins can undergo limited intracellular assembly to form dimers or trimers that could be intermediates during extracellular assembly. However, monomers that have been excluded from assembly are detected in cell culture medium. Difficulties in expressing full-length fibrillin-1 have so far precluded detailed assessment of whether fibrillin can self assemble. However, microscopy studies indicate that assembly occurs in association with cell surfaces and predict a key role for receptors in this process. Subsequent time-dependent microfibril maturation in the ECM could reflect association with other molecules or transglutaminase crosslink formation. Both fibrillin and elastin interact with chaperones in the secretory pathway, but more work is needed if we are to understand how cells coordinate the production of microfibrillar molecules and elastin during elastic fibre formation, and how they prevent uncontrolled or inappropriate intracellular interactions.
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Mouse models |
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Fibrillin-1
Pereira and co-workers have created a gene-targeted mouse model for Marfan
syndrome to test a dominant-negative pathogenesis model in which they replaced
central exons 19-24 of the fibrillin-1 gene with a neomycin-resistance (neo)
expression cassette, reducing the expression of the fbn1 mutant
allele (designated mg) by more than tenfold. Heterozygous
fbn1wt/mut (mg
/+) mice express very low levels of
mutant protein and are morphologically and histologically indistinguishable
from wild-type mice. Homozygous fbn1mut/mut
(mg
/mg
) mice produce only small amounts of mutant fibrillin-1,
appear normal at birth but die of vascular complications prior to weaning.
Some mice show thinning of the proximal aortic wall, which suggests that they
experience aneurysmal dilatation as in human Marfan syndrome. Substantially
reduced extracellular fibrillin-1 staining but normal elastin staining
suggests that organised elastic fibres could accumulate in the absence of
normal fibrillin-1-rich microfibrils.
A second fibrillin-1 mutant mouse line (designated the mgR allele),
accidentally created as a result of aberrant ES cell targeting, has an 80%
reduction in expression of normal fibrillin-1
(Pereira et al., 1999).
Heterozygous mice appear normal at birth and throughout adult life. Homozygous
mice gradually develop severe kyphosis and die of Marfan-like vascular
complications at about 4 months. Newborn homozygous mice have normal vascular
anatomy and architecture, including aortic medial elastic lamellae. However,
fibrillin hypomorphism appears to trigger a secondary sequence of
cell-mediated events, which begin with focal calcifications in the aortic
elastic lamellae, progress to intimal hyperplasia, monocytic infiltration of
the media, fragmentation of elastic lamellae and loss of elastin content, and
finally result in aneurysmal dilatation of the aortic wall.
Tight skin (Tsk) mice are a naturally occurring strain that
harbours a large in-frame insertion in the fibrillin-1 gene
(Kielty et al., 1998;
Gayraud et al., 2000
). The
mutant protein, which is synthesised, secreted and incorporated into the ECM,
is
450 kDa rather than 350 kDa. Heterozygous mice provide a well
documented model of scleroderma, and perturbations in the extracellular
organisation of fibrillin-1 correlate with increased TGFß
availability.
Chaudry and co-workers recently described fibrillin-2 null and fibrillin-2
mutant mice (Chaudry et al.,
2001). The classical shaker-with-syndactyly (sy) mice
harbour a radiation-induced mutation that results in auditory/vestibular
defects together with fusion of the digits (syndactyly) and early lethality.
Positional cloning demonstrated that the syndactyly phenotype is caused by
loss-of-function mutations in the fibrillin-2 gene. Mutations in the
sy allelic series of mice include deletion of the fibrillin-2 gene,
premature termination in which homozygotes have no detectable fibrillin-2
protein, and in-frame exon 38 deletion (part of the fourth TB module), which
may cause a molecular kink; the resulting syndactyly ranges in severity from
hard tissue to soft tissue fusion. The syndactyly could be due to aberrant
fibrillin-2-rich microfibrils in the cartilaginous limb skeleton or altered
availability of TGFß family growth factors. A second fibrillin-2-knockout
mouse has now been described (Arteaga-Solis
et al., 2001
), revealing that syndactyly is caused by defective
mesenchyme differentiation rather than reduced apoptosis of interdigital
tissues. Further analysis identified a functional interaction between
fibrillin-2-rich microfibrils and bone morphogenetic protein 7 (BMP-7)
signalling which, when disrupted, may lead to syndactyly.
Studies of elastin-null mice have confirmed that elastin is an essential
determinant of arterial morphogenesis (Li
et al., 1998a; Li et al.,
1998b
). The mice die of obstructive arterial disease, which
results from subendothelial cell proliferation and reorganisation of smooth
muscle, but not endothelial damage, thrombosis or inflammation. Hemizyous mice
have an increased number of lamellar units in the ascending and descending
aorta consistent with early developmental compensatory alterations in vessel
wall structure. The hemizygous mice phenotype is similar to SVAS, which may be
a disease of haploinsufficiency.
Fibulin-1-null mice exhibit vascular wall weakness, which could involve
elastic fibre defects (Kostka et al.,
2001). Homozygotes die 1-2 days after birth owing to rupture of
blood vessels and massive haemorrhages, and also display kidney (glomerular
malformation or podocyte disorganisation) and lung pathology (delayed alveolar
development). Unexpectedly, fibulin-2-null mice have no obvious phenotype.
Fibulin-5-null mice exhibit a severely disorganised elastic fibre system
throughout the body (Nakamura et al.,
2002
; Yanagisawa et al.,
2002
). They survive to adulthood but have a tortuous aorta with
loss of compliance, severe emphysema and loose skin. These tissues contain
fragmented elastin but no increased elastase activity, which suggests they
have defects in elastic fibre assembly rather than stability.
Fibrillin-1-null mouse models have provided new insights into the Marfan phenotype. Haploinsufficiency or expression of low levels of an allele product that has dominant-negative potential is associated with mild skeletal phenotypes, whereas abundant expression of a dominant-negative allele product leads to a more severe Marfan phenotype. The fibrillin-1 Tsk mice phenotype does not overlap with Marfan syndrome, reflecting instead a gain-of-function that has altered TGFß regulation and excessive fibrosis. Fibrillin-2-null and -mutant mice exhibit recessive syndactyly, indicating a loss-of-function possibly associated with altered BMP-7 activity. Targeted deletion of elastin causes structural and cellular vessel wall abnormalities and altered haemodynamics, indicating a role for elastin in regulating smooth muscle cell proliferation and stabilising arterial structure. Defects in elastic fibre formation in fibulin-5-null mice suggest a key role for this pericellular matrix molecule in cell-matrix interactions. Although these models have provided valuable insights into the physiological roles of several microfibril and elastic fibre molecules, the lack of elastic fibre phenotype in other knockout mice could either reflect compensatory mechanisms or the fact that these molecules are not critical to elastic fibre formation and function.
Future perspectives
Elastic fibres are large and complex, but still surprisingly poorly
understood, ECM macromolecules. They are important because they endow critical
mechanical properties on elastic tissues and regulate cell fate in developing
tissues such as blood vessels. The major challenges ahead are to establish how
cells regulate microfibril and elastic fibre assembly, to define the temporal
hierarchy and repertoire of molecular interactions in assembly and to resolve
their molecular composition. The biomechanical properties of tissue
microfibrils and microfibril-elastin composites, and their molecular basis,
must be better understood. At the whole organism level, virtually nothing is
yet known about how elastic fibres influence cell behaviour, and so
identification of cellular receptors, signalling responses and growth factor
relationships is a priority. Together, these approaches will provide a new
level of understanding of elastic fibre biology that, in turn, should lead to
new strategies for elastic fibre repair and regeneration in ageing and
disease.
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