Jp. Cassella et al., AN ULTRASTRUCTURAL, MICROANALYTICAL, AND SPECTROSCOPIC STUDY OF BONE FROM A TRANSGENIC MOUSE WITH A COL1.A1 PRO-ALPHA-1 MUTATION, Bone, 15(6), 1994, pp. 611-619
A line of transgenic mice have been investigated that expressed modera
te levels of an internally deleted human gene for the pro alpha(I) cha
in of type I procollagen. These mice expressed the gene at approximate
ly 50% that of the endogenous gene. The gene construct was modeled aft
er a sporadic in-frame deletion of the human gene that produced a leth
al variant of osteogenesis imperfecta by causing biosynthesis of short
ened pro alpha(I) chains. Periera et al. (1993) reported extensive fra
cturing in these mice with femurs that were shorter in length and bone
that had decreased ash weight, mineral, and collagen content. These w
orkers demonstrated an increased brittleness in bone using biomechanic
al measurements. The functional consequences of these mutant genes wer
e examined in both transgenic and in normal littermate mice to determi
ne if a valid model at the ultrastructural and analytical level had be
en produced for OI. X-ray microanalysis of bone mineral demonstrated a
significantly lower calcium-to-phosphorus (Ca/P) molar ratio in trans
genic mouse bone than in normal littermates; this was a feature of hum
an OI bone. Fourier transform infrared spectroscopy confirmed that the
mineral present was apatitic in nature despite the lower Ca/P molar r
atio. Alizarin red skeletal staining showed the presence of multiple f
racture calluses on the ribs and on the long bones of some of the tran
sgenic mice, this was not seen on normal littermates. No light microsc
opic differences were observed between normal and transgenic mice; how
ever, many ultrastructural correlates with human OI were observed in t
he transmission electron microscope. Anomalous fibrils associated with
type I collagen, and an amorphous calcified material was observed lin
ing the cartilage, extending beyond the lamina limitans in young trans
genic mice.