Brittle IV Mouse Model for Osteogenesis Imperfecta IV Demonstrates Postpubertal Adaptations to Improve Whole Bone Strength

• Published in: Journal of bone and mineral research Vol. 19; no. 4; pp. 614 - 622
• Main Authors: Kozloff, Kenneth M, Carden, Angela, Bergwitz, Clemens, Forlino, Antonella, Uveges, Thomas E, Morris, Michael D, Marini, Joan C, Goldstein, Steven A
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01-04-2004; American Society for Bone and Mineral Research
• Subjects: Adaptation, Physiological; Aging - physiology; Amino Acid Substitution - genetics; Anatomy, Cross-Sectional; Animals; Biological and medical sciences; biomechanics; Bone Density - genetics; Bone Density - physiology; Bone Development - genetics; Bone Development - physiology; Bone Matrix - physiology; collagen; Collagen Type I - genetics; Disease Models, Animal; Femur - anatomy & histology; Femur - diagnostic imaging; Femur - physiopathology; Fundamental and applied biological sciences. Psychology; knock‐in; Male; Mice; Mice, Transgenic; Minerals - metabolism; mouse model; osteogenesis imperfecta; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - physiopathology; Radiography; Skeleton and joints; Spectrum Analysis, Raman; Stress, Mechanical; Tensile Strength - physiology; Vertebrates: osteoarticular system, musculoskeletal system; Animal model; Puberty; mouse model; Rodentia; knock-in; Osteoarticular system; Biomechanics; Vertebrata; Mammalia; Mouse; Collagen; Osteogenesis imperfecta; Bone; Strength; Adaptation
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/JBMR.040111

The Brtl mouse model for type IV osteogenesis imperfecta improves its whole bone strength and stiffness between 2 and 6 months of age. This adaptation is accomplished without a corresponding improvement in geometric resistance to bending, suggesting an improvement in matrix material properties.
Introduction: The Brittle IV (Brtl) mouse was developed as a knock‐in model for osteogenesis imperfecta (OI) type IV. A Gly349Cys substitution was introduced into one col1a1 allele, resulting in a phenotype representative of the disease. In this study, we investigate the effect of the Brtl mutation on whole bone architecture, strength, and composition across a range of age groups.
Materials and Methods: One‐, 2‐, 6‐, and 12‐month‐old Brtl and wildtype (WT) mice were analyzed. Femurs were assessed at the central diaphysis for cortical geometric parameters using μCT and were subsequently mechanically tested to failure by four‐point bending. Matrix material properties were predicted using μCT data to normalize data from mechanical tests. Raman spectroscopy and DXA were used to assess matrix composition.
Results: Our findings show a postpubertal adaptation in which Brtl femoral strength and stiffness increase through a mechanism independent of changes in whole bone geometry. These findings suggest an improvement in the material properties of the bone matrix itself, rather than improvements in whole bone geometry, as seen in previous mouse models of OI. Raman spectroscopic results suggest these findings may be caused by changes in mineral/matrix balance rather than improvements in mineral crystallinity.
Conclusions: Our findings parallel the currently unexplained clinical observation of decreased fractures in human OI patients after puberty. The Brtl mouse remains an important tool for investigating therapeutic interventions for OI.