what-when-how
In Depth Tutorials and Information
CHAPTER
21
Animal Models of Osteogenesis
Imperfecta
Charlotte L. Phillips, Stephanie M. Carleton and Bettina A. Gentry
University of Missouri, Columbia, MO, USA
produce type I collagen, leading to vascular failure.
15-18
The Mov-13
−/−
phenotype can be rescued in cell culture
and early in development by introduction of a fully func-
tional
Col1a1
gene.
19,20
Heterozygote (Mov-13
/+
) mice
are considered haploinsufficient with a phenotype simi-
lar to human OI type I
14
and survival into young adult-
hood.
21
Mov-13
/+
mice produce structurally normal
type I collagen, though only about 50% of wild-type
levels.
15,22
Mov-13
/+
mice display a disorganized der-
mal collagen matrix,
15
reduced mineralization and
biomechanical strength with an increase in skeletal brit-
tleness.
15,22
Some Mov-13
/+
mice do not exhibit an obvi-
ous bone fragility phenotype, which has been attributed
to bone tissue mosaicism, further complicating experi-
mental interpretation.
15
The mutation exhibits incom-
plete penetrance, as seen by a lack of tooth pathology
and the ability of the odontoblasts and 5% of the osteo-
blasts to transcribe and translate type I collagen in Mov-
13
−/−
, indicating the Mov-13 allele disrupts transcription
in a tissue-specific manner.
15,23
Non-mineralized tissues/
systems impacted by this mutation include liver and the
hematopoietic system.
24
Major weaknesses of this model
include its transgenic nature, early lethality of homozy-
gotes and absence of an equivalent human gene defect.
Animal models have played a major role in under-
standing the pathogenesis of osteogenesis imperfecta
(OI), contributing to our knowledge of the etiology of
disease and evaluation of multiple organ systems and
treatment strategies. At least 15 animal models have been
identified or generated since 1983, representing a wide
array of mutations and a broad range of clinical out-
comes and molecular/biochemical mechanisms. Three
primary mechanisms have emerged, each with represen-
tative animal models: (1) defects in type I collagen genes
(
COL1A1
and
COL1A2
), which produce the majority of
OI cases,
1-3
(2) defects in post-translational hydroxy-
lation of type I procollagen and ER trafficking4-7
4-7
and
(3) abnormalities in type I procollagen chaperone activ-
ity.
8-10
In the following sections individual OI animal
models are described and subdivided by their most rep-
resentative pathogenic mechanisms. In addition,
Table
21.1
provides a summary including the Mouse Genome
Informatics (MGI)/International Mouse Strain Resource
(IMSR) strain name, relevant human OI classification,
genetic background and commercial availability of spe-
cific models as a research resource.
11-14
TYPE I COLLAGEN GENE DEFECTS
(
Col1a1
AND
Col1a2
)
Human
COL1A1
Minigene Mouse (
COL1A1
)
The human
COL1A1
minigene mouse is another early
transgenic model of OI generated by two constructs con-
taining portions of the human
COL1A1
gene. The first
minigene construct contained 11 kb of the promoter, first
five exons/introns and the last six exons/introns.
25
The
second construct is the same but had a deletion remov-
ing most of the regulatory sequence of the first intron.
25
Mov-13 Mouse (
Col1a1
)
The Mov-13 mouse, the earliest OI mouse model
described, is a transgenic model with an integrated
Moloney leukemia virus located at the 5′ end of the
first intron of the pro-α1(I) collagen gene, resulting in
a null α1(I) allele.
15-17
Homozygous Mov-13
−/−
mice
die between gestation days 11 and 12 due to failure to
