The broad goal of this proposal is to determine the cell type that mediates focal bone loss induced by transient muscle paralysis. Specifically, transient muscle paralysis rapidly induces focal osteoclast mediated trabecular and cortical bone loss though a RANKL mediated process. Additionally, activated T-cells have been shown to mediate focal osteoclastogenesis in models of acute bone loss through similar RANKL pathways. This proposal will explore the hypothesis that activated T-cells mediate focal bone loss induced by transient muscle paralysis. To explore this general hypothesis, an integrated approach combining engineering and biological techniques (murine model of acute bone loss, high-resolution in vivo bone imaging, image registration and manipulation, flow cytometry, genetically and pharmaceutically altered mice, and immunoflourescent imaging) will be used to pursue three Specific Aims.
These Aims will include: 1) defining the resolution of proximal tibia metaphysis trabecular image registration, 2) determining if activate T-cells are acutely up-regulated following transient muscle paralysis, and 3) determining if activated T-cells are co-localized with the initiation sites of bone resorption in the proximal tibia metaphysis following induction of transient muscle paralysis. This fellowship combines a novel quantification approach with a model of rapidly induced osteoclastogenesis to assess whether a likely candidate mediator cell, T-cells, are spatially and temporally associated with sites where bone resorption first occurs. As this model provides the unique ability to study the interaction between muscle function and bone homeostasis, the primary findings in this fellowship will yield clinically relevant insights into the link between aging related degeneration of muscle mass (sarcopenia) and similar age related decreases in bone mass (osteoporosis).
This project is focused on experimentally identifying a candidate cell type that mediates focal bone loss induced by transient muscle paralysis. From a clinical perspective, the findings in this proposal would provide relevant insight into a potential causal relationship between aging related degeneration of bone mass (osteoporosis) and muscle mass (sarcopenia).
|Ausk, Brandon J; Huber, Philippe; Srinivasan, Sundar et al. (2013) Metaphyseal and diaphyseal bone loss in the tibia following transient muscle paralysis are spatiotemporally distinct resorption events. Bone 57:413-22|
|Ausk, Brandon J; Huber, Philippe; Poliachik, Sandra L et al. (2012) Cortical bone resorption following muscle paralysis is spatially heterogeneous. Bone 50:14-22|