Bone resorption is a multistep process initiated by attachment of osteoclasts and their precursors to bone, prompting cytoskeletal reorganization and activation of intracellular signaling pathways. In fact, by mechanisms poorly understood, the integrin alphavbeta3, which recognizes bone matrix-residing proteins, is essential to osteoclastic bone resorption, in vitro and in vivo, and is therefore a potential anti-osteoporosis target. Optimizing this therapeutic goal will depend, however, on detailed analysis of the integrin's molecular structure as it relates to specific components of the resorptive process, information presently not available. Acquisition of alphavbeta3, structure/function data will be best achieved by expressing, in alphavbeta3 null osteoclasts, constituents of the integrin whose individual impact on particular events in the resorptive process, can be evaluated. In this regard, we developed a series of tools which, we propose, will enable us to achieve these goals. First, we generated beta3 knockout mice with deranged osteoclasts. Second, we have established a retroviral-based technique of reconstituting beta3-/-osteoclasts with beta3 cDNAs. Third, we utilized TAT technology to deliver full length proteins, into entire populations of osteoclasts and their precursors. These tools provide the unique opportunity to identify constituents of the beta3 integrin subunit which regulate specific aspects of osteoclast physiology in authentic bone resorptive cells. We focus on the cytoplasmic domain of the beta3 integrin subunit as it is known, in other circumstances, to regulate cytoskeletal organization and mediate matrix derived signals. The fact we have completely rescued the beta3-/-integrin osteoclast phenotype by retroviral transduction of a full length human beta3 cDNA positions us to delineate the cytoplasmic components of this integrin which govern specific events the resorptive process. We hypothesize that specific components of the beta3 integrin cytoplasmic domain: 1) regulate activation of intraosteoclastic signaling molecules involved in the resorptive process; 2) organize the osteoclast cytoskeleton; 3) regulate the capacity of osteoclasts to degrade bone in vitro and in vivo. Thus, our Specific Aims are to identify specific components of the beta3 integrin cytoplasmic domain which: 1) regulate activation of intraosteoclastic signaling molecules involved in the resorptive process; 2) organize the osteoclast cytoskeleton; 3) regulate the capacity of osteoclasts to degrade bone in vitro and in vivo.
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