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In Depth Tutorials and Information
any GAG attachment domains. Versican was originally
identified in hyaline cartilage, but was later found to be
expressed in most smooth muscle tissues, fibrous and
elastic cartilage, the central and peripheral nervous sys-
tem, basal layer of the epidermis, some glandular epi-
thelia and in blood vessels.
69
Versican was found to be
important in cell proliferation, migration and angiogen-
esis and is generally considered to be an anti-adhesive
molecule that plays a central role in tissue morphogen-
esis and maintenance.
69
Versican has been shown to be
expressed in early osteoid formation.
70,71
When bone
tissue develops and moves towards more advanced
developmental stages (woven to lamellar bone forma-
tion), mRNA expression of versican decreases.
71
During
osteoblast differentiation, increased levels of versican
core protein expression are observed; however, no con-
cordance was detected between the changes in levels
of gene and protein expression.
71,72
Interestingly, osteo-
blasts involved in deposition of lesional bone in fibrous
dysplasia of bone (OMIM #174800) produce a bone
matrix enriched in versican.
73
Aggrecan, encoded by the
ACAN
gene located on
human chromosome 15,
74
is highly expressed in carti-
lage extracellular matrix.
75
The protein core of aggrecan
consists of three globular domains and multiple GAG
attaching domains (CS and KS). Its negatively charged
GAG chains attract water, resulting in hydrostatic pres-
sure that is crucial for the biomechanical properties of
cartilage.
76,77
Aggrecan has two splice variants; one con-
tains an epidermal growth factor-like sequence while
the other does not.
78
Expression of aggrecan is not
restricted to cartilage; under certain conditions, osteo-
blasts are also able to express aggrecan.
79
Aggrecan-
deficient mice are characterized by having cleft palate
and short limbs, tail, and snout. They die perinatally as
a result of respiratory failure. The heterozygotes show
dwarfism and develop spinal misalignment with age,
which result in spastic gait and death by starvation.
Histologic examination reveals a high incidence of ver-
tebral disc chondrocyte degeneration.
77,80
Mutations in
human aggrecan cause short stature and skeletal abnor-
malities, chondrodysplasia and spondyloepiphyseal
dysplasia type Kimberley (SEDK) (OMIM #608361), a
subtype of heterogeneous skeletal dysplasias character-
ized by shortening of the trunk and limbs.
81
Perlecan, an extracellular/pericellular heparan
sulfate proteoglycan, is encoded by the
PLC
gene on
human chromosome 1 and is a major component of all
basement membranes.
82,83
It has a large multidomain
protein core with three sulfated GAG chains (usually
HS) attached to it. The C-terminal is the domain vital
for supramolecular assembly of, and cell connection to,
the basement membrane.
84
It is synthesized by vascu-
lar endothelial, articular cartilage and smooth muscle
cells and has been shown to be involved in basement
membrane type IV collagen fibril assembly during
healing.
85,86
Perlecan is also present in the ECM of long
bone growth plates, particularly in chondrocytes transi-
tioning from the resting zone to the proliferating zone
of the growth plate, which undergo dramatic glycosyl-
ation changes.
86-88
The lack of HS or even decreased
sulfation of the GAG chains can decrease perlecan's
ability to interact with matrix proteins, thereby modu-
lating matrix assembly and cell proliferation and adhe-
sion.
89
Perlecan binds to members of the FGF growth
factor family, increasing the bioavailability and activity
of these growth factors
90
resulting in enhanced prolif-
eration and differentiation of chondroblasts, osteoblasts
and preosteoblastic cells. This enhanced FGF activa-
tion can also increase neovascularization;
91
leading to
improved osseous regeneration.
92
Moreover, adding
purified HS-decorated perlecan to bone graft substi-
tutes in osseous repair applications increases the num-
ber of adherent osteoblast and preosteoblastic cells,
which favors better bone regeneration.
92
Most perlecan-
deficient mice die prenatally, but those that survive
display disorganized growth plates and develop skel-
etal dysplasia characterized by shortened and bowed
long bones, as well as craniofacial abnormalities, and
die shortly after birth. Histological analysis of the car-
tilage of these animals showed they have severe disor-
ganization of the columnar structures of chondrocytes
and defective endochondral ossification.93,94
93,94
Human
mutations in the perlecan gene lead to Silverman-
Handmaker-type dyssegmental dysplasia (OMIM
#224410) and Schwartz-Jampel syndrome type 1 (SJS1)
(OMIM #255800), both rare diseases causing, among
other clinical features, short-limbed dwarfism, myo-
tonic myopathy, dystrophy of epiphyseal cartilages and
joint contractures.
95,96
CELL SURFACE PGS
This group includes two major subgroups: syndecans
(1-4) and glypicans (1-6). Syndecans, which in mam-
malian cells are expressed by genes located on differ-
ent chromosomes, are single pass integral membrane
spanning proteins with a cytoplasmatic domain.
97
Syndecan family members display distinct ectodo-
mains but share homologous transmembrane and cyto-
plasmatic domains. Their core proteins carry three
to six HS and/or CS chains.
98,99
They are subdivided
into two classes based on the existence of GAG bind-
ing sites at both the amino- and carboxyl-terminal end
of the ectodomain (syndecan-1 and -3), or only in the
carboxyl-terminal domain (syndecan-2 and -4). Different
syndecans are expressed in a cell-specific manner and
