what-when-how
In Depth Tutorials and Information
alteration in PG (decorin) expression in OI cases com-
pared to healthy controls.
136
Other reports demon-
strated higher levels of PG immunostaining in bone
samples of OI patients,
2,137
suggesting that different
subtypes of OI may present different PG depositions.
One case of severe OI accompanied by barely detectable
amounts of secreted decorin was reported, while a sec-
ond patient with a mutation in the exact same position,
who did not present with such a severe phenotype had
normal levels of decorin expression and secretion, lead-
ing the authors to speculate that the absence of deco-
rin in the first patient resulted in a more severe clinical
phenotype.
133
Cultured trabecular osteoblasts derived
from OI patients did not demonstrate the normal time-
dependent increase in total proteoglycan and proteo-
glycan matrix deposition compared to non-OI controls.
3
Some post-translational modifications to the PG's GAG
chains correlate with normal individuals' chrono-
logical age.
N
-sulfation of HS, for example, increases
more than three-fold postnatally, and the degree of
O
-linked modifications to CSPG and biglycan decrease
linearly with age.
137
In contrast, HS chains derived
from OI osteoblastic cells failed to express the normal
age-dependent increase in
N
-sulfation and decrease
in
O
-linked modifications, indicating these cells fail to
follow a developmental differentiation pattern and are
stalled in a fetal-like state.
19,137
It should be noted that other PG-modifying enzymes
could also be important in OI. For example, mutations
in EXT1 and 2, the genes coding for the enzymes which
catalyze the polymerization of HS,
138
are the cause of
multiple exostoses, a group of genetic syndromes char-
acterized by inappropriate boney outgrowths mainly
adjacent to the growth plate.
139,140
Another enzyme
likely to be critical to bone is heparanse, an endogly-
cosidase that cleaves the HS side chains of HSPGs,
141
which when overexpressed in mice leads to shorter
long bones and an increased bone mass phenotype.
142
There are numerous other enzymes that regulate the
synthesis and degradation of PGs and their GAG
chains; however, a full description of these enzymes
and their effect on bone is beyond the scope of this
chapter.
determine whether any of the cases of OI not attributed
to mutations in collagen or their modifying enzymes
could be caused by mutations in one of the PG genes
that populate bone tissue. This could, in turn, lead to
new concepts in treating what can often be a devastat-
ing skeletal disease.
References
CONCLUDING REMARKS
It is now clear that the numerous and diverse types
of the proteoglycans have important roles in regulating
both the structure and function of mineralized tissue.
The total amount and character of the proteoglycans
is altered in the bones of OI patients. Mouse models
deficient in PGs mimic many aspects of OI, leading to
the conclusion that the role of collagen and PGs must
be related functionally. It will next be important to
