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decreased skin strength.
107
The
Ppib
−/−
mouse phenotype
appears milder than human with fewer fractures; mice
typically die at 40-50 weeks of age. Molecularly, without
CypB significant amounts of collagen remain in the ER.
Patients with null
CRTAP
mutations usually die during
the perinatal period. The
CRTAP
−/−
mouse phenotype
is milder than that in many human patients. By qBEI,
Fratzl-Zelman et al. compared the bone mineralization
density distribution in
CRTAP
−/−
mice as well as in bone
samples from children with type VII OI with decreased
CRTAP expression.
105
Though type VII OI patients with
CRTAP
mutations have severe fractures at birth as well
as bone deformities and impaired growth,
105
fractures
are not observed in
CRTAP
−/−
mice.
5
The
CRTAP
mouse
is maintained on a mixed 129Sv/ev-C57Black/6J genetic
background
105
as well as on a pure C57BL/6J back-
ground.
5
The occurrence of perinatal lethality is more
prevalent in mice with a pure C57BL/6J background.
5
CRTAP
−/−
mice have increased bone turnover with
decreased bone formation even though osteoblast and
osteoclast numbers are equivalent to wild-type mice.
104
CRTAP impacts multiple tissues including skeletal, skin,
cartilage, lung and kidney.
Equine Model: [Hereditary Equine Regional
Dermal Asthenia (HERDA)]
A Ppib missense mutation (glycine-to-arginine sub-
stitution at position 39) is linked to a recessive hyper-
extensible fragile skin disorder in American Quarter
Horses.
108,109
Abnormal skin fragility in affected horses
results in the development of severe lacerations and
hematomas with minor trauma, frequently resulting in
disfiguring scars; there is no bone phenotype. HERDA-
affected horse skin demonstrates ultrastructurally smaller
diameter collagen fibers, though
Ppib
−/−
mice have larger
fibers with ER retention.
107
The molecular mechanism of
the skin response remains to be elucidated.
P3H1
−/−
Mouse
Exons 1-3 of the P3H1 or leprecan 1 (
Lepre1
) gene
were deleted by homologous recombination to create
the
P3H1
−/−
null mouse.
106
Heterozygous
P3H1
/+
mice
do not exhibit any observable phenotype.
P3H1
−/−
mice
exhibit delayed postnatal growth with shortening of
their long bone segments (rhizomelia) and are smaller
with decreased BMD relative to wild-type and
P3H1
/+
littermates.
106
P3H1
−/−
mice develop kyphoscoliosis
which progressively worsens with age. Femoral stiff-
ness and force to failure is significantly lower in
P3H1
−/−
mice compared to
P3H1
/+
and wild-type mice.
106
Type I
collagen-rich tissues, tendon and skin, are also impacted
by the mutation;
P3H1
−/−
mouse tail tendons have abnor-
mal morphology and demonstrate an increase in small
diameter fibrils,106
106
with an altered distribution of fibril
sizes ranging from 20 to 100 nm compared to a range of
50 to 400 nm in wild-type mice.
P3H1
−/−
skin is thinner
than that of wild-type mice, and the reticular dermis has
relatively normal looking collagen fibrils interspersed
with clumped areas of fibrils and open spaces not seen in
wild-type skin.
CHAPERONE: FOLDING AND SECRETION
INTO THE MATRIX
Serpinh1
(
Hsp47
−/−
) Mouse
Hsp47, a collagen-specific molecular chaperone-like
protein, is coded for by the SERPINH1 (serpin peptidase
inhibitor, clade H (heat shock protein 47), member 1,
(collagen binding protein 1)) gene.
110,111
Recently, homo-
zygous missense mutations in
SERPINH1
were associ-
ated with a severe recessive deforming form of OI (type
III).
8
Hsp47 transiently associates with collagen triple
helices in the ER where it functions in correct folding
and stabilization of the triple helices; it dissociates prior
to collagen transfer into the cis-Golgi.
110
The
Hsp47
−/−
knockout mouse was generated by classical targeting
inactivation strategy prior to recognizing Hsp47's role
in the collagen triple-helix folding and stabilization.
112
The
Hsp47
−/−
mouse exhibits embryonic lethality by day
11.5 postcoitus, yet heterozygous
Hsp47
/+
mice appear
normal.
Hsp47
−/−
embryos had few detectable collagen
fibers and abnormal epithelial tissues, as well as vascular
ruptures.
112
Hsp47
−/−
fibroblasts secrete type I procolla-
gen, which was sensitive to protease and assembled into
poorly aligned triple helices. OI patients with
SERPINH1
mutations had minor amounts of detectable Hsp47, sug-
gesting small amounts of Hsp47 are sufficient to prevent
the severe phenotype.
Hsp47
−/−
embryonic lethality is a
disadvantage of this model.
CypB
(
Ppib
−/−
) Mouse
CypB
knockout mice were recently developed by tar-
geting exon 3 using homologous recombination and the
cre-lox strategy.
107
Homozygous
CypB
(
Ppib
−/−
) mice
have many features similar to patients including reduced
body size, weight and decreased BMD compared to
wild-type.
107
Ppib
−/−
mice also have severe kyphosis
visible at 8 weeks which progressively worsens.
Ppib
−/−
mice have reduced amounts of femoral total bone vol-
ume and trabecular bone, and increased skin laxity and
Canine Model:
SERPINH1
(L326P)
A
SERPINH1
missense mutation was identified in a
dog model (rough-coated dachshund) with a severe form
