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

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 _CT and were subsequently mechanically
tested to failure by four-point bending. Matrix material properties were predicted using _CT 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.