Classical osteogenesis imperfecta (OI) is caused by mutations in the two genes encoding type I collagen. OI is associated with low bone mass and abnormally high bone matrix mineralization. The Brtl/+ OI mouse is a knock-in model caused by a glycine substitution in one COL1A1 allele. Brtl/+ pups display 30% perinatal lethality; survivors have small size and brittle bone. Unexpectedly, homozygous Brtl/Brtl pups, producing only mutant collagen, have normal survival rates and a rescued phenotype with normal bone fragility. We investigated whether the rescued bone fragility is reflected in bone matrix mineral content.
To further examine the roles of matrix homogeneity vs insufficiency in matrix mineralization, we crossed Brtl/+ mice with Mov13, a murine model with a null COL1A1 allele, to obtain Brtl/Mov compounds. To determine bone phenotype, we obtained cortical cross sectional area, whole bone four point bending data and bone mineralization density distributions (BMDD) by quantitative backscattered electron imaging, using 2-month-old heterozygous Brtl/+, homozygous Brtl/Brtl, Mov13 and Brtl/Mov mutants (n=812 per group).
Cross-sectional area and ultimate load were significantly lower in Brtl/+, similar in Brtl/Brtl, and significantly higher in Mov/+ and Brtl/Mov, compared to WT. Analysis of bone matrix mineralization showed that mean (CaMean) and most frequent (CaPeak) calcium concentrations were similar in Brtl/Brtl and WT but significantly higher in all other groups compared, indicating an OI phenotype of the bone material in Brtl/+, Mov/+ and Brtl/Mov mutants while in Brtl/Brtl bone matrix mineralization was normalized.
These results indicate that in Brtl/Brtl mice bone mechanical properties and hypermineralization of the matrix are rescued by matrix homogeneity with mutant collagen, while Brtl/Mov mutants have increased bone strength due to increased cross-sectional area compared to WT. However, the hypermineralization associated with severe matrix insufficiency is not normalized despite the bone size adaptation.
17 May 2014 - 20 May 2014