Multiscale Mechanics of Bone: Examining the Influence of Genetic Alterations
Miller, Brendyn J
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This MSc thesis investigates how genetic alterations involved in the synthesis of proteins or in the regulation of tissue remodeling affects the composition, structure and mechanics of bone at the multiscale levels. This was accomplished by performing two mouse model studies. In the first study, bone properties of TIMP-3 knock-out (Timp-3⁻ˊ⁻) mice were examined by performing mechanical testing, µCT analysis, and FTIR analysis. Results demonstrated that the mechanical integrity of the Timp-3⁻ˊ⁻ bone was compromised. Decreased values for the yield and ultimate load, stress capacity, and fracture toughness were observed in both the TIMP-3 deficient bones. These reductions in the mechanical and material properties were attributed to alterations in the bone structure and composition. The Timp-3⁻ˊ⁻ cortical bone was less dense, thinner, and exhibited increase porosity and the trabeculae in the cancellous bone were thinner, more interconnected, and more tightly packed together. The composition of the Timp-3⁻ˊ⁻ bone were found to have altered mineralization and increased compositional heterogeneity. These geometric and compositional changes suggest that there is increased bone remodeling, possibly due to increased matrix metalloproteinase (MMP), disintegrinmetalloproteinase (ADAM), and disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) activity, resulting from a lack of TIMP-3. These results therefore suggest that TIMP-3 is crucial for maintaining optimal bone tissue during growth and development. In the second study, the cochlear intracortical structure of genetically modified oim mice, a mouse model of osteogenesis imperfecta (OI) or brittle bone disease, was examined to gain insight on the possible causes of hearing loss, typical in severe cases of the disease. The results from the image analysis demonstrate that the oim bone is much more porous with more populated and interconnected canals within the cochlea. This higher porosity, possibly due to high bone turnover in these mice, may lead to reduced bone fracture toughness, thus increasing the risk of consequent bone deformities and the likelihood of hearing loss. Both studies showed how genetic mutations at the nano-scale level can result in reduced mechanical properties of the bone at the macro-scale level. It is therefore crucial to correct any biological alterations at any level of the hierarchy to maintain the healthy bone structure. These studies provide a deeper understanding of the bone material and will ultimately lead to the development of new treatments for skeletal pathologies.