title: An ultrastructural, microanalytical, and spectroscopic study of bone from a transgenic mouse with a COL1.A1 pro-alpha-1 mutation.
abstract: A line of transgenic mice have been investigated that expressed moderate levels of an internally deleted human gene for the pro alpha (I) chain of type I procollagen. These mice expressed the gene at approximately 50% that of the endogenous gene. The gene construct was modeled after a sporadic in-frame deletion of the human gene that produced a lethal variant of osteogenesis imperfecta by causing biosynthesis of shortened pro alpha (I) chains. Periera et al. (1993) reported extensive fracturing in these mice with femurs that were shorter in length and bone that had decreased ash weight, mineral, and collagen content. These workers demonstrated an increased brittleness in bone using biomechanical measurements. The functional consequences of these mutant genes were examined in both transgenic and in normal littermate mice to determine if a valid model at the ultrastructural and analytical level had been produced for OI. X-ray microanalysis of bone mineral demonstrated a significantly lower calcium-to-phosphorus (Ca/P) molar ratio in transgenic mouse bone than in normal littermates; this was a feature of human OI bone. Fourier transform infrared spectroscopy confirmed that the mineral present was apatitic in nature despite the lower Ca/P molar ratio. Alizarin red skeletal staining showed the presence of multiple fracture calluses on the ribs and on the long bones of some of the transgenic mice, this was not seen on normal littermates. No light microscopic differences were observed between normal and transgenic mice; however, many ultrastructural correlates with human OI were observed in the transmission electron microscope. Anomalous fibrils associated with type I collagen, and an amorphous calcified material was observed lining the cartilage, extending beyond the lamina limitans in young transgenic mice.
authors.affiliation: Department of Experimental Pathology, University of London, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Cassella
authors.forename: R
authors.initials: R
authors.lastname: Pereira
authors.forename: J S
authors.initials: JS
authors.lastname: Khillan
authors.forename: D J
authors.initials: DJ
authors.lastname: Prockop
authors.forename: N
authors.initials: N
authors.lastname: Garrington
authors.forename: S Y
authors.initials: SY
authors.lastname: Ali
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004577:Electron Probe Microanalysis; D005269:Femur / Q000378:metabolism / Q000648:ultrastructure*; D005786:Gene Expression Regulation / Q000235:genetics*; D006132:Growth Plate / Q000378:metabolism / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000648:ultrastructure; D010013:Osteogenesis Imperfecta / Q000235:genetics; D010758:Phosphorus / Q000378:metabolism; D011347:Procollagen / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D011347:Procollagen; D010758:Phosphorus; D002118:Calcium