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altered mineral/matrix composition architecture and
structural organization. Quantitative second harmonic
generation (SHG) imaging microscopy of
oim/oim
bone
showed disorganized collagen structure, resulting in a
weaker matrix
66
with decreased mineral:matrix ratio due
to decreased collagen content and thinner mineral crys-
tals than
oim
/+
and wild-type mice.
52
Small-angle X-ray
scattering (SAXS) of
oim/oim
tibias showed an isotro-
pic orientation of the crystals instead of normal parallel
orientation.
57
FTIR (Fourier transform infrared) analy-
sis revealed decreased carbonate content and CO
3
:PO
4
ratio
49,56
and quantitative backscattered electron imaging
(qBEI) suggested that
oim/oim
bones have a higher cal-
cium content than wild-type bones. Neutron activation
analysis revealed alterations in mineral composition of
femurs and incisors of
oim/oim
mice compared to wild-
type femurs.
47
Light and scanning electron microscopy
showed that
oim/oim
and
oim
/+
teeth exhibit changes in
pulp chamber size, reduced numbers of dental tubules
and abnormal dentin mineralization, with
oim/oim
teeth
being more severely affected than
oim
/+
.
61
The disor-
dered extracellular matrix serves as an abnormal tem-
plate for mineral deposition, leading to altered bone
density as well as mineral crystals of abnormal shape,
size, composition and alignment.
52
The brittleness of
oim/oim
bone appears to be mostly related to the mineral
phase, possibly due to abnormal interaction between the
mineral phase with the collagenous matrix phase.
52
At the cellular level,
oim/oim
mice have increased
osteoclast number and size, and increased resorptive
activity compared to wild-type.
67
Immature osteoblasts
from
oim/oim
mice have increased RANKL/OPG ratio
and TNF expression compared with wild-type mice, fur-
ther supporting elevated bone turnover in OI.
68
Several non-skeletal collagen containing tissues
have also been extensively evaluated, including ten-
don, skin, heart, aorta, muscle and kidney.
Oim/oim
tendons have less collagen, smaller cross-sectional
areas, disrupted quasi-crystalline lateral order of col-
lagen, and lower tensile strength than wild-type ten-
dons.
54,64,69
These differences are speculated to be due
to altered collagen crosslinking.
54,63
The
oim/oim
heart
had decreased ventricular chamber stiffness, and fewer
and smaller perimysial collagen fibers compared to
wild-type.
70
The descending aorta of
oim/oim
mice have
reduced breaking strength and decreased elastic modu-
lus relative to wild-type.
59,71
Oim/oim
mice also have a
skeletal muscle pathology with smaller muscles and
decreased contractile generating force.
60
Also unique
to the
oim
mouse is a type I collagen glomerulopathy.
Oim/oim
mice accumulate homotrimeric type I collagen
in their glomeruli.
58,72,73
Though
oim
/+
mice synthesize
both heterotrimeric and homotrimeric type I collagen,
the sclerotic glomerular collagen is 95-98% homotri-
meric, suggesting homotrimeric type I collagen is the
pathogenic isotype of type I collagen in glomerular
disease.
73
In addition to extensive characterization of mul-
tiple organ and tissues the
oim
model has been used
to evaluate different treatment strategies including
transplantation of bone marrow stroma, hematopoi-
etic cells, and fetal blood stem cells,
74-79
as well as treat-
ment with growth factor,
80,81
bisphosphonate
43,82-87
or
a RANK-Fc.
88-90
Intrauterine transplantation of fetal
blood stem/stromal cells shows decreased bone brittle-
ness in offspring by improving the mechanical integ-
rity of the bone at the molecular, tissue and whole bone
levels.
74
Additionally, transplantation of hematopoietic
stem cells resulted in increased trabecular number and
thickness with a concomitant decrease in trabecular spac-
ing in bone.
78
Treatment of
oim/oim
mice with either a
bisphosphonate or a RANK-Fc causes similar decreases
in fracture incidence with increases in metaphyseal bone
volume via increased number of thinner trabeculae.
90
Although the
oim
mouse is the most widely used
mouse model of OI, the
oim
gene defect, which causes
the absence of functional α2(I) chains, is a rare cause of
OI in the human population, and thus a limitation of
this model.
91,92
In humans, mutations in the
COL1A2
gene resulting in the absence of functional pro-α2(I) col-
lagen chains have also been shown to be associated with
the connective tissue disorder, Ehlers-Danlos syndrome
and activation of nonsense-mediated decay pathways
eliminating the
COL1A2
transcripts in these individu-
als.
92-95
The
oim/oim
mouse is most similar molecularly,
biochemically and phenotypically to a child with OI type
III as a result of homozygosity for a 4-bp deletion in the
coding region of the
COL1A2
gene corresponding to the
carboxy-terminal end.
91,92,96
The
oim
mutation is maintained on an outbred back-
ground B6C3Fe
a/a
(Jackson Laboratory, Bar Harbor,
ME), and recently has been transferred to congenic
strains, allowing for easier interpretation of phenotype-
genotype studies and identification of modifier genes.
45,51
G610C
Amish Mouse (
Col1a2
)
The
G610C
is the first mouse model of OI to model a
large human OI population in both genotype and phe-
notype.
97
The model is based on an Amish OI type I/IV
population of 64 individuals in 37 nuclear families who
are all heterozygous for the same glycine-to-cysteine sub-
stitution at position 610 (
G610C
) of the α2(I) chain.
97
The
knockin
G610C
mouse was created by a cre/lox strategy
with a targeting vector containing a loxP flanked neomy-
cin resistance cassette which introduced the point muta-
tion into the
col1a2
gene. The initial homozygote mice
(
G610C/G610C
Neo+
) still carried the neomycin cassette as
well as the
G610C
mutation and were viable. However,
once this mouse was crossed with a cre-recombinase
