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associated with dentiogenesis imperfecta.
29
Following
puberty, femoral strength and stiffness increase, with a
decrease in long bone fractures, which is attributed to
adaptations of the material properties of the extracellular
matrix rather than to structural bone alterations.
33
BrtlIV
/+
bones have increased levels of microdamage compared to
wild-type.
34
BrtlIV
/+
mice also develop progressive osteo-
arthritis (OA) beginning at 2 months of age, with severe
OA-marked sclerosis of the subchondral bone and joint
space narrowing by 12 months of age.
35
BrtlIV
/+
mice express normal levels of
Col1a1
and
Col1a2
transcripts and produce type I collagen molecules
with three different chain compositions in the expected
1:2:1 ratio [α1(I)
2
α2(I):α1(I)α1(I)
G349C
α2(I):α1(I)
G349C
2
α2(I)].
36
Abnormal trafficking of collagen molecules with a sin-
gle mutant chain leads to the accumulation of collagen
in the endoplasmic reticulum (ER) resulting in delayed
secretion, overmodification and selective degradation.
36
Differences between the perinatal lethal and nonlethal
moderate BrtlIV
/+
pups appears associated with acti-
vation of ER stress-related protein [CHOP/Gadd153
(growth arrest and DNA damage inducible gene)] in cal-
varia of lethal BrtlIV
/+
mice, whereas nonlethal BrtlIV
/+
calvaria have increased expression of the chaperone-like
heat shock protein, αB crystalline, which may be protec-
tive against osteoblast apoptosis.
37
ER stress and cellular
malfunction may be major contributors to the BrtlIV/
BrtlII phenotype.
32,36-39
Once α1(I)α1(I)
G349C
α2(I) is
secreted from cells, it is efficiently incorporated into col-
lagen fibrils and forms crosslinks with the same efficiency
as α1(I)
2
α2(I).
36,40
Collagen fibrils in the BrtlIV
/+
bone
matrix exhibit greater variability in D-periodicity spac-
ing and morphology,
41
which may affect the type and
amount of mineral deposited.
42
The phenotype of BrtlIV
/+
mice may be related more to abnormal function of mutant
fibroblasts and osteoblasts than to abnormal structure or
function of collagen secreted by these cells.
32,40
Interestingly, homozygosity for the mutant allele
(BrtlIV
−/−
) leads to matrix homogeneity resulting in a
less severe phenotype. These mice model a mild type IV
OI with no rib fractures or flared thorax, normal BMD
and no lethality.
3
BrtlIV
/+
mice have been used to test therapeutic
treatment strategies for OI including bone marrow and
bisphosphonate treatments.
38,39,43
In utero
transplanta-
tion of adult bone marrow donor cells eliminated the
perinatal lethality of BrtlIV
/+
mice, with improvement
of femoral geometric and biomechanical properties.
38
Alendronate treatment improved BrtlIV
/+
femoral geom-
etry and load response before fracture, but decreased
predicted material modulus and strength. It also exhib-
ited detrimental effects on osteoblasts and matrix syn-
thesis, as well as retention of mineralized cartilage.
43
A distinct strength of the BrtlIV
/+
mouse is that it models
a human OI patient.
30
Potential weaknesses include the
transgenic nature of the BrtlIV mouse and the unknown
impact of the L359M substitution and the engineered
ribozyme sequence. The maintenance of this mutation
on a mixed genetic background (Sv129/CD-1/C57BL/6S
and C3H/HEJ/CD-1/C57BL6) may more closely reflect
the heterogeneity of genetic background found in
patients with OI, but may make interpretation of geno-
type-phenotype correlations more difficult.3,29,30,33,37,44
3,29,30,33,37,44
OIM
Mouse (
Col1a2
)
The osteogenesis imperfecta murine (
oim
), the most
widely studied mouse model of OI, was originally iden-
tified at the Jackson Laboratory (Bar Harbor, ME) due to
its small size and skeletal deformities.
45
The
oim
model's
disease causing mutation is a naturally occurring spon-
taneous single nucleotide deletion in the
Col1a2
gene
that results in a frameshift, altering the carboxy-terminal
amino acid sequence of pro-α2(I) collagen.
45,46
The
abnormal carboxy-terminal end of the mutant pro-α2(I)
collagen chain prevents it from associating with pro-
α1(I) collagen chains.
45,46
As a result homozygous (
oim/
oim
) mice produce solely homotrimeric type I collagen
[α1(I)
3
] instead of the normal heterotrimeric type I colla-
gen [α1(I)
2
α2(I)], causing a non-lethal, recessive OI type
III phenotype.
45
At birth,
oim/oim
mice often have hemor-
rhages into joint cavities, and fractures in the long bones
of the legs and tail vertebrae.
Oim/oim
mice are smaller
than wild-type or heterozygote (
oim
/+
) littermates with
reduced body mass, reduced bone mineral content
(BMC) and BMD, cortical thinning, bowing of the long
bones with fractures and callus formation.
45,47-49
Oim/
oim
femurs and tibias exhibit osteopenia, disorganized
cortical lamellae, fewer medullary and more gracile tra-
becular spicules, and progressive skeletal dysplasia.
45,47
Biomechanical testing of
oim/oim
femurs by 3-point and
4-point bending and torsional loading to failure demon-
strated that
oim/oim
femurs have reductions in maximum
load, stiffness and energy to failure compared to wild-
type mice.
48-52
Oim
/+
mice have a milder OI phenotype,
modeling OI type I in humans, with bone biomechanical
integrity intermediate to wild-type and
oim/oim
bone.
48-50
Oim
/+
body size, body weight, bone weight, femoral cor-
tical area and thickness, BMD and BMC are similar to
wild-type throughout life.
47,48,51
Cortical bone in
oim
/+
mice contains areas of normal lamellar bone intermixed
with areas of bone hypercellularity.
50
This model has been extensively studied to evaluate
the role of α2(I) collagen chains in type I collagen struc-
ture and function,
53,54
and the consequences of produc-
ing only homotrimeric type I collagen on mineralized
and non-mineralized tissues.
47,48,54-62
Oim
α1(I)
3
homotri-
mers exhibit altered thermal stability,
53,63
microunfold-
ing pattern,
53
collagen-collagen forces,
64
fibrillogenesis
kinetics
53
and thermodynamics.
65
Oim/oim
bones have
