Spatio-temporal regulation of cortical bone remodeling

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Bone is a dynamic tissue with the capacity to remodel to renew and adapt its internal microarchitecture. The evolution of this process reaches back to the Silurian (444 million years ago) and enabled the rise of large long-lived terrestrial animals, including humans. Through closely coupled osteoclastic resorption and osteoblastic formation, remodeling repairs damage and optimizes the structural and material properties of bone. This adaptation requires precise spatio-temporal coordination of these disparate cell types into transient partnerships known as Basic Multicellular Units (BMUs) which replace discrete packets of bone called secondary osteons. Remodeling carried out by BMUs is critical for the long-term maintenance of healthy bone. Conversely, disruption of BMU regulation lies at the root of chronic diseases like osteoporosis, undermines stability of implants, hinders integration of tissue grafts/engineered scaffolds, and even impedes extraterrestrial exploration/colonization due to the loss of bone in low gravity. Despite centuries of study, our understanding of the regulation of BMUs in space and time remains rudimentary due to a lack of in situ (3D) and in vivo (4D 3D over time) data. Indeed, many STEM fields including biology, mathematics, engineering and material science currently strive for a better understanding of bone remodeling and all are challenged by the lack of empirical data. As a consequence, much of this field remains theoretical and increasing looks to in silico computational modeling to bridge gaps in knowledge. To directly address these limitations, Dr. Cooper's research group has been at the forefront of the application of advanced imaging (conventional and synchrotron) to study the impacts of aging, adaptation and disease on the microarchitecture of the outer (cortical) shell of bone. The current proposal specifically aims to further hone a novel rabbit-based platform for the dynamic 4D tracking of individual BMUs using the Canadian Light Source synchrotron (Theme 1) and then to deploy this innovative approach to directly test long-standing regulatory hypotheses for the first time (Theme 2). Key questions that will be addressed include: 1) Are BMUs random in their distribution or are they actively targeted towards stimuli such as damage? 2) Are the size, direction and progression of BMUs dynamically impacted by biomechanical factors such as tissue strain induced by loading? Answering these and related questions will advance our understanding of the evolutionary and developmental information encoded within bone microarchitecture and, in turn, yield wide ranging impacts in bone biology spanning from materials engineering to palaeontology. Ultimately, the fundamental insights generated will help inform the development of improved biomedical strategies (behavioral, pharmaceutical, surgical, etc.) to mitigate the profound human and economic costs of bone diseases which afflict millions and cost billions worldwide.