Animal Models of Osteogenesis Imperfecta - Osteogenesis Imperfecta - page 185

of autosomal recessive OI. 113,114 Clinically the dogs exhib-
ited osteopenia, spontaneous bone and teeth fractures,
joint hyperlaxity and frequent early loss of homozygous
animals. 113,114 The affected dachshunds are homozygous
for a naturally occurring spontaneous L326P (leucine-to-
proline substitution at position 326) missense mutation
in the SERPINH1 gene. There is not an equivalent human
OI patient and the molecular mechanism remains to be
elucidated. The dachshund represents a larger animal
model which may model the human bone more closely
than mouse. However, large animals are more expensive
to maintain, and dog breeder's interests are typically to
eradicate lethal or debilitating alleles from the purebred
dog gene pool. 114

Online Mendelian Inheritance of Animals (OMIA) data-
base, 11,12,118 all of which are valuable resources for inves-
tigators desiring to use such animal models.

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Osterix Null ( Sp7 −/− ) Mouse
Osterix null ( Sp7 −/− ) mice lack a functional osterix
gene and die within 15 minutes of birth due to respira-
tory insufficiency.115 115 Grossly, bones are hypoplastic, bent
and deformed; histological examination demonstrates
an almost absent mineralized skeleton, lack of bone tra-
beculae and no fusion of joints. 115 Markers of osteoblast
differentiation are severely reduced, while markers of
osteoclasts were normal, suggesting a lack of mesenchy-
mal cell differentiation into osteoblasts with a concomi-
tant lack of bone development. 115 This model underscores
the importance of osterix during bone development;
however, early lethality of the mice make it difficult to
study the role of osterix during growth and adulthood.
The Sp7 −/− conditional knockout mouse generated using
a cre/lox strategy 116 is phenotypically normal at birth, but
begins to display an osteopenic phenotype by 8 weeks
of age, which persists at 16 weeks of age (adulthood).
Growing and adult mice display reduced mineraliza-
tion, BMD, bone formation rate, thinner and more porous
cortical bones and immature trabeculae similar to those
seen in newborn mice. 116 Osteoclasts, chondrogenesis and
growth plate morphology are normal at all ages exam-
ined. 116 This model allows for the study of early skeletal
development and maturation as well as further elucida-
tion of the signaling pathway involved in osteogenesis.
Currently only a single human patient carrying a frame-
shift of the SP7 gene has been described. 117
In summary, animal models have been instrumental
in elucidating the genetic, molecular, biochemical and
pathophysiology of OI as well as expanding our under-
standing of connective tissue structure and function.
Animal models are critical to the evaluation of poten-
tial therapeutic strategies and approaches. Presented
here is the current status of characterized OI animal
models ( Table 21.1 ). However, as new models are con-
tinually identified and generated they can be found in
the Mouse Genome Informatics (MGI) database, the
International Mouse Strain Resources (IMSR) and the