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have been shown to mediate cell binding, signaling,
migration, proliferation, cytoskeletal organization and
cell-matrix interactions. 100 Syndecan functions in all
cells can be divided into four categories:
Glypicans are associated with the basement mem-
brane of the cell surface via a glycosylphosphatidylino-
sitol (GPI) moiety anchor. To date, six members of this
family have been identified (designated 1-6) and they
are divided into two subclasses (glypican-1, -2, -4, -6
and glypican-3, -5) based on their amino acid sequence
homology. 120,121 The HS attachment site is close to the
C-terminus of the core protein, in close proximity to
the cell surface. 122 The main function of membrane-
attached glypicans is to regulate the signaling of Wnts,
Hedgehogs, FGF and various members of the BMP fam-
ily, thereby playing a role in the control of cell division
and growth regulation. 123-125 Whether they stimulate or
attenuate the signaling pathway specifically depends
on their context. 122 Interestingly, the HS chains are not
mandatory for glypican's described regulatory roles in
signaling, but membrane attachment via the GPI anchor
is required. 123,125,126
As MC3T3-E1 pre-osteoblast cells progress in vitro
from a proliferative phase to a differentiative phase,
they decrease their CS and/or DS PGs expression (bigly-
can, decorin and versican) and increase the levels of HS
core protein gene expression, in particular glypican-1
and -3. 127 Reduced glypican-3 abrogates the expres-
sion of the osteogenic transcription factor, Runx2, and
thus differentiation, while adding Runx2 to cultures
results in increased expression of glypican-3, pointing
to a feedback mechanism. 127 Glypican loss-of-function
mutations are associated with delayed endochondral
ossification,128,129 128,129 leading to developmental overgrowth.
Glypican-3-deficient mice display prenatal and post-
natal skeletal overgrowth and skeletal abnormalities
associated with marked reduction in calcified trabecu-
lar bone and an abnormal persistence of hypertrophic
chondrocytes. These features resemble Simpson-Golabi-
Behmel syndrome (SGBS) (OMIM #312870), an X-linked
condition characterized by pre- and postnatal over-
growth, coarse facies, congenital heart defects, and other
congenital abnormalities. 123,130,131
1. Receptor activation: syndecans are known to bind
many growth factors (such as FGFs, VEGF, TGF-β,
fibronectin and antithrombin-1) and present them
to their respective receptors, thus enhancing their
bioavailability. 98,99,101
2. Providing structural support by binding to ECM
molecules such as collagens. 98,99,102
3. Supporting cell-cell adhesion. 103-105
4. Suppression of tumor proliferation and
progression. 106,107
Syndecans are developmentally and transiently
expressed in the limb bud and many times form dimers
or oligomers, a structure that may be important for their
functions as it enhances their ability to bind growth fac-
tors. 108,109 Syndecan-1, -2 and -3 are expressed in areas of
endochondral and periosteal bone, making them impor-
tant factors in osteogenesis. 109 Osteoprotegerin (OGP), a
soluble decoy receptor for RANKL, has been shown to
contain a heparin-binding domain 110,111 and studies sug-
gest that cells internalize and degrade OPG through its
binding to syndecan-1. 112 In addition, syndecan-1 was
shown to be involved in OPG-induced chemotaxis. 113
In vitro studies show syndecan-2 expression in condyle
progenitor cells during differentiation into osteoblasts. 114
Syndecan-2 was also shown to induce osteoblastic cell
apoptosis in vitro . 115 Normal syndecan-3 expression is
restricted and confined to the proliferative zone of the
growth plate of developing long bones, where it par-
ticipates in the outgrowth and proliferation of the limb,
regulates the onset of chondrogenesis, osteogenesis
and joint formation, as well as playing a role in regulat-
ing the proliferation of epiphyseal chondrocytes during
endochondral ossification.116,117 116,117 As the growing bone's
elements develop further, syndecan-3 gene expression
decreases in the diaphyseal periosteum, while becom-
ing stronger around the early epiphysis. As the disphy-
seal periosteum initiates osteogenesis and gives rise
to the intramembranous bone collar, syndecan-3 gene
expression increases again in the inner layers of the
periosteum along the diaphyses. 117 In addition, proper
syndecan-3 expression in the proliferative zone of the
growth plate plays a role in the appropriate expression of
Indian hedgehog (IHH) in the prehypertrophic zone. 116
Interference with syndecan-3 function inhibits local cell
proliferation and results in undergrowth and severe skel-
etal abnormalities. 118 Syndecan-4 is widely expressed in
chondrocytes and osteoblasts, 114 and its expression has
been demonstrated to be upregulated in osteoarthritis.
Inhibition of syndecan-4 expression reduces cartilage
destruction in mouse models of osteoarthritis (OA). 119
DIRECT ASSOCIATION BETWEEN OI
AND PG
The glycine substitutions in α2(I) collagen that cause
the lethal OI subtype occur in eight regularly spaced
clusters that align with proteoglycan-binding sites. 132
Similarly, the α1(I) Gly415Ser/Cys mutation is also
thought to involve the PG binding site, 133 indicating a
direct association between PGs and OI manifestation.
Conflicting results regarding PG expression and secre-
tion in OI were reported in different in vitro and in vivo
studies. In some reports, subnormal amounts of PGs
and/or their GAG chains were isolated from bones of
OI patients. 4,134,135 Some reports, however, show no
 
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