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the phenotype in bone but not in cartilage,
97
but the pre-
cise role of this enzyme in the OI phenotype is not yet
known.
All these observations provide insight into the miner-
alization processes in normal individuals and in OI. To
the best of current knowledge, in general, the mineraliza-
tion process in OI seems to be delayed because the col-
lagen or the way it gets into the matrix is altered. We do
not yet know if it is the defective collagen alone, or the
altered association of matrix proteins with the collagen
that affects the mineralization process. Preliminary data
based on remineralization of decalcified NCP-free and
NCP containing wild-type and OI model bones suggests
that the retarded mineralization in OI varies with the
nature of the mutation. The wild-type mouse collagen
matrix alone does not remineralize as well as the matrix
that still contains NCPs, but in the oim
/
oim mice and the
fro
/
fro mice the collagen matrix itself mineralizes more
rapidly. We believe that this is because the NCPs are not
bound to the right position on the collagen matrix.
NCPs
Osteoblast
Synthesize, Process,
Export, Collagen
Fibrils
X
NCPs bind to
specific sites on
Collagen
X
Ca & P
X
Alk P activity
increased
X
HA nucleation
X
Growth of HA crystals
Growth and
Proliferation of
Mineralized ECM
X
CONCLUSIONS
With few exceptions bones of humans with OI and
mouse models of these human conditions have increased
mineral contents associated with a decreased collage-
nous matrix. The crystal size is smaller and the orienta-
tion of the crystals in most cases is less well organized.
Altered crystal properties and histological and biochemi-
cal composition are found in all cases, but the type of
alterations differs with age, nature of the mutation and
sometimes gender. To date none of the therapies has
been completely effective in correcting the mineral and
matrix abnormalities, but via their study much is being
learned about the mineralization mechanism in OI and in
normal individuals.
FIGURE 4.7
Cartoon illustrating mineralization mechanisms and
how they might be altered in different types of OI after the formation
of the osteoblast. The X indicates where defects might exist in OI.
Enzymes that are involved in synthesis of collagen,
its processing and its preparation for mineralization
have occasionally been found to be defective in OI. For
example, the pro-collagen peptidase (BMP1
/
tolloid) that
cleaves the terminal ends from the triple helix was found
to mutate in two patients with autosomal recessive type
I OI.
92
Of even greater significance are the mutations in
the complex that is involved in putting one molecule of
3′-hydroxyproline in type I collagen, as all of the com-
ponents of this enzyme complex have defects in several
OI variants.
93
Additionally collagen processing requires
chaperones to assist in the formation and transport of the
triple helix, and several of these chaperones are associ-
ated with other variants of OI.
94
Alkaline phosphatase, an enzyme whose activity
increases in parallel to bone mineralization, is reduced
in activity in all classic types of OI as compared to age-
matched controls.
95
There have been no studies of its
activity in other forms of OI. Other enzymes that would
not be expected to be related to OI may also be mutated.
For example, the fro
/
fro mouse, which was the result of
chemical mutagenesis, has a mutation in sphingosine
phosphodiesterase 3.
96
Rescue of the bone phenotype by
return of Smpd3 with a collagen type I promoter rescued
Acknowledgments
The authors work as described in this publication was supported
by NIH grants DE04141, AR043125, AR046121. The authors appre-
ciate the contributions of Dr. Nancy Pleshko (Temple University),
Dr. Cathleen Raggio (Hospital for Special Surgery), Dr. Rhima
Coleman (University of Michigan), Dr. Joan Marini (NIH), Ms. Erin
Carter (Hospital for Special Surgery) and technicians Ms. Mila Spevak
and Ms. Lyudmila Lukashova to these studies.
References
