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

Abstract

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 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.

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

“…Femurs from Brtl mice had reduced maximum load compared to Wt at three months of age [25]. However, by 12 months of age, Brtl femurs were able to resist the same loads as Wt femurs [25]. This is consistent with observations that post-pubertal fracture number tends to decrease in OI patients [23].…”

“…This is consistent with the observation that bone from OI patients plays "catch-up" with increasing age in an attempt to compensate for the reduction in the amount and integrity of the bone [24]. The Brtl and Mov-13 mouse models of OI have also shown age-associated changes in bone integrity [25,32]. Both of these models carry mutations in the α1(I) chain and only the heterozygote animals have been evaluated.…”

“…The Mov-13 model is a transgenic model carrying a murine retrovirus in the first intron of the COL1A1 gene resulting in a null allele and an OI type I-like phenotype [46]. Femurs from Brtl mice had reduced maximum load compared to Wt at three months of age [25]. However, by 12 months of age, Brtl femurs were able to resist the same loads as Wt femurs [25].…”

“…Femora and tibiae from wildtype (Wt), heterozygous (oim/+) and homozygous (oim/oim) animals of each of the two genetic backgrounds (the inbred C57BL/6J and the outbred B6C3Fe) were evaluated at 1, 2 and 4 months of age, corresponding to childhood, adolescence and post-puberty in humans [25] using a multi-tiered approach described in the materials and methods. To define the bone biomechanical integrity we measured the ability of the femoral diaphysis to resist torsional loading as determined by the torsional ultimate strength T max , torsional stiffness K s , and strain energy to failure U, which are a function of both the geometry (cross-section shape and size) and bone biomechanical material properties, as defined by tensile strength Su and shear modulus of elasticity G. Bone biomechanical material properties are in turn a function of the bone composition that can be further subdivided into contributions from the organic component (mainly type I collagen) and mineral component (primarily hydroxyapatite).…”

Osteogenesis imperfecta

“…Resistance to fracture, quantitatively determined in mouse models of osteogenesis imperfecta such as in osteogenesis imperfecta murine (oim) mice (carry ing a point mutation in Col1a2 in the region encoding the C propeptide, preventing the incorporation of the α2(I) chain into the collagen heterotrimer) and brittle IV (Brtl/+) mice (a point mutation in Col1a1 that causes the Gly349Cys substitution in the α1(I) chain and the synthesis of an overmodified type I collagen), was found to be reduced 124,125 . The increased vulnerability to frac tures might be explained by abnormalities of the miner alized matrix at different levels, affecting structures that normally hinder crack propagation 126 .…”