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The Contributions of FAK and PyK2 to Osteoclast Functions and Bone Homeostasis

Ray, Brianne Jeriel
Thesis/Dissertation; Online
Ray, Brianne Jeriel
Parsons, Thomas
Bouton, Amy
Bullock, Timothy
Bender, Tim
Cross, Janet
Bone homeostasis is associated with constant bone remodeling, a process that involves the balanced activity of bone-degrading osteoclasts and bone-forming osteoblasts. When either of these processes becomes deregulated, pathological bone phenotypes arise and bone becomes either too dense or too porous. The clinical implications associated with osteoclast activity are considerable, and understanding the molecular mechanisms through which these cells function is imperative for developing therapies that can prevent osteoclast-mediated diseases. The research described in this thesis is dedicated to elucidating the relative contributions of the FAK family signaling molecules to osteoclast functions in vitro and bone remodeling in vivo. The FAK family consists of two members, FAK and Pyk2, and while both are known to be expressed in osteoclasts, this research demonstrates that FAK and Pyk2 expression is upregulated during osteoclast differentiation. Furthermore, data presented herein indicates that FAKdeficiency in osteoclasts results in a modest impairment in in vitro bone resorption. However, this deficiency does not translate to increased bone volume in vivo, as would be expected, for mice with a conditional deletion of FAK in myeloid-derived osteoclasts (FAK myeloid ) were found to have similar bone volume as control animals. This thesis also extends our knowledge of the contribution made by FAK and Pyk2 to podosome dynamics in osteoclasts, which are critical for bone resorption. FAK-deficient osteoclasts have normal podosomes, while Pyk2 -/- osteoclasts exhibit disrupted podosome belts. Interestingly, FAK was found to partially compensate for a loss of Pyk2, as the organization of podosomes was more significantly altered in FAK myeloid /Pyk2 -/- osteoclasts than in Pyk2 -/- knockout cells. Therefore, FAK and Pyk2 work in concert to ii regulate signaling pathways required for podosome dynamics. Cytokine signaling is imperative for osteoclast differentiation and function and, prior to this research, FAK had not been implicated in cytokine signaling in osteoclasts. We demonstrate that FAK is required to fully augment activation of ERK in response to M-CSF, thus shedding light on specific signaling networks in osteoclasts that are dependent upon FAK. Together, this research demonstrates that Pyk2 plays a more dominant role than FAK in osteoclast function, but the partial redundancy between FAK and Pyk2 indicates that dual inhibition may be critical for optimal control of osteoclast-mediated bone destruction. Note: Abstract extracted from PDF text
University of Virginia, Department of Microbiology, PHD, 2011
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