Advanced imaging to understand bone's adaptation to mechanical load

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Bone is a dynamic tissue that changes in response to its environment by adding or removing bone depending on the signals it receives. These signals can include mechanical (e.g., loading through exercise) and inflammation (e.g., swelling from an injury). Although bone's response to exercise and other forms of loading have been studied, how bone changes in complex environments with changing mechanical and inflammatory signals is not well understood. Advances in imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) mean that we are now able to study bone and the tissues around bone in living people and animals at the same time, and can better capture changes in bone over time. This means that we can develop a better understanding of how and why bone changes in response to activities such as exercise or bedrest, and how bone interacts with tissues surrounding it. The long-term goal of my research program is to develop and apply advanced imaging techniques to better understand the mechanism by which bone adapts to mechanical signals. The proposed work will use novel imaging techniques using micro-computed tomography (micro-CT, ideal for bone imaging), MRI (ideal for soft tissue imaging) and 3D image registration to test new hypotheses regarding the interaction between mechanical loading and inflammation on quantitative measures of bone adaptation. Over the course of this five year grant, my objective is to apply 3D image registration techniques to quantify bone formation and resorption at sites of interaction between bone and soft tissue to evaluate changes in bone volume and microarchitecture over time. I will examine bone adaptation in two animal models at two points of bone-soft tissue interaction: 1) muscle attachment sites in a well-established muscle disuse model in mice, and 2) bony spur, or osteophyte, formation at the edges of joints in guinea pigs to test the hypothesis that bone's local response to mechanical stimuli is tightly mediated by mechanical interaction with soft tissues such as muscle, ligament and cartilage, while the more distant response is controlled primarily by inflammatory pathways. In the mouse model, I will manipulate mechanical loading by inducing muscle disuse via botulinum toxin injection, while in the guinea pig I will manipulate mechanical loading by altering joint stability via anterior cruciate ligament transection. I will perturb the inflammatory environment using anti-inflammatory drugs. The proposed work will enhance our ability to measure bone changes in living animals, and determine whether inflammation dominates bone loss close to and far from muscle attachment sites as well as bone spur formation after joint injury. The findings from the proposed research program will improve understanding of the stimuli that drive bone formation and resorption, and will have substantial implications for enhancing bone formation in humans.