Osteoclasts, cells that degrade bone, are critical for the maintenance of healthy bones. Altered osteoclast function is implicated in multiple bone disorders such as osteoporosis and osteoporosis. Osteoclast activation is initiated by adhesion to the bone surface, followed by cytoskeletal rearrangement, formation of the sealing zone and polarized ruffled membrane, and directional secretion of acids and lysosomal enzymes onto the resorbing surface. Proline-rich tyrosine kinase 2 (PYK 2) has been identified as a major adhesion-dependent tyrosine kinase in osteoclasts that localizes at the podosomes and tight sealing zones in resorbing osteoclasts. Therefore, it is highly likely that PYK2 will be an essential element in osteoclastic bone resorption. However, the exact means by which PYK2 regulates osteoclast function remains unclear. Whether PYK2 and its family member, focal adhesion kinase (FAK) regulate osteoclastic cytoskeletal organization and bone resorption in a redundant fashion or in a coordinated manner is the central question of this proposal. Based on our preliminary results, we hypothesize that pYK2 and FAK are mutual inhibitors of each other, functioning in a coordinated manner to regulate podosome assembly and osteoclastic bone resorption. To test this hypothesis, we will: 1. Examine whether PYK2 activity and podosome localization are inhibited by FAK in osteoclasts. 2. Examine whether FAK is phosphorylated and down regulated by PYK2 in osteoclasts. 3. Investigate the roles of PYK2 and FAK in regulating podosome assembly and osteoclastic bone resorption.
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