Cryo analytical microscopy of cell-mediated mineralization in models of bone disease

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The bone mineralization process is crucial in maintaining the mechanical integrity of bone, from the time of its development to its constant remodeling throughout life. The process of pathologic mineralization and bone remodeling and how cells control these processes, is very poorly understood in vivo. By characterizing unique animal models of bone pathologies, spanning both lack and increase of bone, this project will elucidate the process of cell-regulated mineralization during endochondral ossification, the mineralization process that occurs during growth of long bones, and also during adult remodeling. We will also investigate how a defect in mineralization affects the mineral content, composition and organization of the collagen fibrils and mineral in pathological bones. We will first map healthy (wildtype) mineralization, focusing on the cell regulated mineralization, mineral composition and structure in bone and calcified cartilage. We will then investigate how the cell regulated mineralization alters in hypomineralized bone models, which have been reported as abnormalities of skeletal development. Finally, we will study the bone remodeling in under and over producing bones in leukemia and parathyroid hormone (PTH) treated animal models. To address these problems, this work will combine multiscale, state of the art imaging and analysis techniques from dynamic live animal imaging (cellular level) to spatially resolved nanoscale (mineral and collagen fibrils) analytical techniques to characterize the processes by which bone mineralizes, remodels and also any alterations in these processes between healthy and pathologic tissues. Insight into skeletal cellular mineralization mechanisms in pathologic tissues could guide tissue engineering approaches for restoring bone and help to identify targeted treatments.