Graduate Defense: Scott Birks

Dissertation Information

Title: Role Of Mechanical Signaling In Bone Tissue

Program: Doctor of Philosophy in Materials Science and Engineering

Advisor: Dr. Gunes Uzer, Mechanical and Biomedical Engineering

Committee Members: Dr. Julia Oxford, Biological Sciences; Dr. David Estrada, Materials Science and Engineering and Electrical and Computer Engineering; Dr. Sarah Manske, Materials Science and Engineering

Abstract

As the global population ages and life expectancy continues to rise, osteoporosis continues to be a growing worldwide health concern. The International Osteoporosis Foundation reports that 1 in 3 women over the age of 50 years and 1 in 5 men worldwide will experience osteoporotic fractures in their lifetime, costing between 5 and 6.5 trillion USD annually in Canada, Europe, and the United States alone. The need for preventative measures to reduce age-related bone loss is clear, not only to improve the quality of life for countless individuals but also to relieve the economic burden this condition imposes.

Exercise is a proven preventative method as it increases and maintains bone density, and reduces the risk of osteoporotic fracture with age. The benefits of exercise are not only mediated by physiological changes but also by mechanically challenging the tissue. The work presented here seeks to elucidate how attenuating cellular mechanotransduction from embryogenesis through adolescence and into adulthood affects bone quality before and after exercise, as well as how exposure to whole-body low-intensity vibration from adulthood into old age affects bone quality before and after exercise.

Linker of Nucleoskeleton and Cytoskeleton (LINC) protein complexes play an important role in cellular structure by connecting cytoskeletal elements to the nuclear envelope, as well as being critical regulators of force transmission from the cytoskeleton to the nucleus in vitro. We hypothesized disrupting these complexes in vivo would lead to decreased bone quality outcomes. To investigate LINC function in vivo, we generated two Cre/lox murine models that disrupt the LINC complex in bone progenitor cells – one under the Prrx1 promoter and the other under the osterix (Osx) marker. Bone microarchitecture and mechanical properties were measured at an 8-week baseline old mice and mice subjected to a 6-week exercise intervention. We found decreased osteogenic and adipogenic differentiation potential of bone marrow aspirates in our Osx model as well as diminished trabecular architecture at an 8-week baseline; however, there were no remarkable changes in bone microarchitecture or mechanical properties after our six-week running intervention. Similarly, our Prrx1 model did not show any bone microarchitecture or mechanical property changes after our six-week running intervention, but this model also did not show cellular phenotype differences or 8-week baseline differences either.

Finally, to investigate how exposure to whole-body low-intensity vibration from adulthood into old age affects bone quality before and after exercise, we subjected 20-week-old female C57Bl/6J mice to a low-intensity vibration (LIV) intervention (0.7g, 90Hz) for 15 minutes/2 times a day/5 days a week until they reach 48 weeks of age. A sub-cohort was placed in a six-week running intervention. We did not see any remarkable changes in bone microarchitecture or bone mechanical properties with long-term LIV treatment or exercise. Understanding the mechanical regulation of bone progenitor cells and how bone tissue responds to long-term physical stimulation in an aging population may lead to improved physiotherapy interventions, reducing the prevalence of osteoporotic fractures.