Ultra-structural defects cause low bone matrix stiffness despite high mineralization in osteogenesis imperfecta mice

Abstract

Bone is a complex material with a hierarchical multi-scale organization from the molecule to the organ scale. The genetic bone disease, osteogenesis imperfecta, is primarily caused by mutations in the collagen type I genes, resulting in bone fragility. Because the basis of the disease is molecular with ramifications at the whole bone level, it provides a platform for investigating the relationship between structure, composition, and mechanics throughout the hierarchy. Prior studies have individually shown that OI leads to: 1. increased bone mineralization, 2. decreased elastic modulus, and 3. smaller apatite crystal size. However, these have not been studied together and the mechanism for how mineral structure influences tissue mechanics has not been identified. This lack of understanding inhibits the development of more accurate models and therapies. To address this research gap, we used a mouse model of the disease (oim) to measure these outcomes together in order to propose an underlying mechanism for the changes in properties. Our main finding was that despite increased mineralization, oim bones have lower stiffness that may result from the poorly organized mineral matrix with significantly smaller, highly packed and disoriented apatite crystals. Using a composite framework, we interpret the lower oim bone matrix elasticity observed as the result of a change in the aspect ratio of apatite crystals and a disruption of the crystal connectivity.

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

“…Failure to observe a change in size/ perfection of mineral crystals in the oim/oim mice does not agree with small angle-scattering reports that oim/oim mice bones had mineral crystals that were thinner and less well oriented on collagen fibrils [21]. These features were confirmed in a recent transmission electron microscopic study [35]. This discrepancy may be the result of the older age of our mice, the small sample size in each group, or a lack of sensitivity of the FTIR imaging methodology.…”

“…The oim/oim mice in a B6C3Fe background (as used in the current study), age 2 months, showed a sexdependent increase in mineral density as measured by quantitative backscatter electron imaging.. Females had greater bone density than did males [35]. FTIR imaging has previously been used to characterize oim/oim mice [8,9]; however, in those studies, data from both sexes were pooled as a result of the small sample size.…”

“…No comparative data exist for children or patients with OI. Because fracture incidence in adults within OI does show sexual dimorphism [35] and, as yet, no study has considered sex dependence of these commonly used drugs in juveniles or adults with OI, we addressed that question in a mouse model, oim/oim. Sexual dimorphism in oim/oim material properties was previously reported for 4-monthold mice (on a C57/BL background) based on measurements of micro-CT, Raman, and mechanical properties [41].…”

Osteogenesis imperfecta

“…by small angle X ray scattering, the thickness of bone mineral par ticles was the same or smaller than in con trols 119,120 . The combin ation of increased matrix mineral content and similar par ticle size implies that mineral par ticles are more tightly packed in the extracellular matrix.…”

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

“…Others have shown the importance of the collagen matrix organization on bone mechanical properties [70,71] and recently we have shown using nanoindentation that compared to wild-type mice, oim have greater mineralization of a poorly organized matrix [72]. Therefore, exogenous cells may have affected the bone mineralization or improved organization of bone matrix collagen fibers in the oim bones at the microscopic matrix scale, potentially in response to production of normal COL1A2.…”