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the dermis, decorin-deficient mice have fragile skin but
no apparent effect on bone mass or architecture at mac-
roscopic or histological levels.
41,42,50
On the other hand,
biglycan-deficient mice present with spontaneous aortic
aneurisms.
51
These mice also fail to achieve peak bone
mass and develop age-dependent osteopenia, which
is attributed to biglycan's role in the proliferation, sur-
vival and differentiation of osteoblast precursors.
42,50,52
Bgn
knockout mice have a decreased number of bone
marrow stromal cells, leading to lower osteoblast num-
ber and activity, increased rate of osteoclast differentia-
tion and activity, reduced response to TGF-β as well as
BMP2 and 4, reduced collagen synthesis and relatively
more apoptosis compared to cells derived from normal
wild-type mice.
15,16,41,50-53
Due to the structural similar-
ity of decorin and biglycan, ablation of one seems to
cause an increased expression of the other. In order to
overcome this compensatory mechanism, double defi-
cient mice were generated. Phenotypic analysis of these
decorin/biglycan double knockouts reveals that the
skeletal phenotype is more severe, developed earlier
and that both the cortical and trabecular bone mass are
severely reduced.
42
Some of these characteristics resem-
ble the clinical manifestations of the progeroid form of
Ehlers-Danlos syndrome (EDS)
42,52
(OMIM:#130070), a
group of heritable connective tissue disorders that share
the common features of skin hyperextensibility, articu-
lar hypermobility, and tissue fragility. The molecular
mechanism appears to be based on increased TGF-β
signaling which shifts some bone marrow stromal cells
from growth to apoptosis, leading to a decreased num-
ber of osteoprogenitor cells and subsequently reduced
bone formation.
11,42
Asporin, encoded by the
ASPN
gene on human chromosome 9,
33
though lacking any
GAG chains is also considered a class I SLRP. It is abun-
dant in cartilage;
54
however, its functions in bone have
yet to be determined.
Fibromodulin and lumican, both class II SLRPs, are
encoded by genes located on human chromosomes
1 and 12, respectively. Both SLRPs have four keratan
sulfate GAG chains. Fibromodulin exhibits a wide tis-
sue distribution, with the highest abundance observed
in articular cartilage, tendon, ligament and throughout
the growth plate.
45,55,56
Lumican is highly expressed in
the cornea and in interstitial collagenous matrices of the
heart, aorta, skeletal muscle, skin, intervertebral discs
and in adult articular chondrocytes.
57,58
Fibromodulin and lumican compete for the same
binding sites on collagen fibrils, but since fibromodu-
lin has two collagen binding sites (one lower- and one
higher-binding affinity) on its core protein, whereas
lumican has only one, fibromodulin has a higher affin-
ity of binding to collagen.
28,29,59
Lumican is expressed
during early fibril assembly, when thinner fibrils are
generated. Apparently, fibromodulin's role is to connect
the small fibrils into large, more mechanically resilient
collagen fibers, thus its expression is upregulated dur-
ing late fibril assembly.
37,43
During fetal endochondral and intramembranous
bone development, fibromodulin is expressed by both
chondrocytes and osteoblasts. Fibromodulin's pericel-
lular deposition is strong around the late-hypertrophic
chondrocytes of the secondary ossification center and in
the growth plate.
60
Fibromodulin-depleted mice demonstrate a sig-
nificant reduction in tendon stiffness, ectopic tendon
ossification and early-onset osteoarthritis. These mice
also showed a marked increase of lumican expres-
sion indicating again a partial rescue/compensatory
mechanism.
57,61
Preliminary analysis of their skeletal
phenotype points to higher bone mass phenotype.
62
Despite the fact that differentiating and mature osteo-
blasts were shown to secrete lumican,
63
lumican-
deficient mice showed no alteration in bone struc-
ture.
43,64
Mice in which the genes encoding both of these
proteoglycans had been knocked out are smaller than
their wild-type littermates and displayed gait abnor-
mality, joint laxity, misaligned patellae, severe knee
dysmorphogenesis, and extreme tendon weakness, all
leading to age-dependent osteoarthritis.
52,56,64
Again,
some of these manifestations phenocopy the clinical
symptoms of EDS (OMIM #130070).
Another member of the class II SLRP family, PRELP,
found on human chromosome 1
65
and known to regu-
late bone mass in mice, appears to be a negative regu-
lator of osteoclastogenesis.
66
Considering that most
members of the SRLP family are found in skeletal tissue
it will be interesting to determine in the future what, if
any, role they have individually or in combination in
regulating bone structure and function.
MODULAR PGS
This PG family is a heterogeneous group character-
ized by the assembly of various protein modules in an
elongated and often highly glycosylated structure. It is
further divided into two subfamilies of hyalectans (hya-
loronic acid- and lectin-binding PGs, such as versican
and aggrecan) and non HA-binding PGs (e.g., agrin and
perlecan).
Versican, a large chondroitin sulfate PG, is charac-
terized by a versatile modular structure. Versican is
encoded by the
VCAN
gene located on human chro-
mosome 5.
67
It has four splice variants, designated V0,
V1, V2 and V3. Variants V0-V2 differ in the length of
their GAG chain attachment domain, having between
five and 15 attachment sites,
68
whereas V3 is devoid of
