Bone mineral properties in growing Col1a2+/G610C mice, an animal model of osteogenesis imperfecta

Abstract

The Col1a2+/G610C knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2+/G610C and their wild-type controls (Col1a2+/+), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2+/G610C with an LRP+/A214V high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2+/G610C tibias had 13% fewer secondary trabeculae than Col1a2+/+, these were thinner (11%) and more widely spaced (20%) than those of Col1a2+/+ mice. Vertebrae of Col1a2+/G610C mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1a2+/+. The cortical bone of Col1a2+/G610C tibias at 2-months had 3% higher tissue mineral density compared to Col1a2+/+; Col1a2+/G610C vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2+/+. FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2+/G610C to Col1a2+/+ at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2+/G610C vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day-old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2month-old vertebral cortices. At age 3-months-of-age, male femurs with both a Col1a2+/G610C allele and a Lrp5 high bone mass allele (Lrp5+/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen α2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments.