Skeletal metastases from breast and prostate cancer are the cause of significant morbidity and mortality. Mechanisms by which skeletal metastases are established are unclear. Drugs that inhibit osteoclast (OC) function (namely bisphosphonates) ameliorate both osteolytic and osteoblastic metastatic bone disease, suggesting that OCs are involved in the pathogenesis of both forms of bone metastases. One approach to examine the role of OCs in skeletal metastases is the use of a mouse lacking the integrin subunit beta3. We have preliminary data that osteolytic bone metastases are significantly decreased in beta3-/- mice. The beta3-/- mouse has two fundamental defects: diminished osteoclast resorption mediated by alpha-v beta3 and diminished platelet aggregation mediated by alphaIIbeta3, both of which may play a role in the establishment of bone metastases. Blockade of platelet/tumor interactions via the beta3 integrin decreases lung metastases in mice, suggesting a role for platelet beta3 integrin in metastases. Given the above facts, we hypothesize that 1) decreased osteolytic metastases in the beta3-/- mouse arise from diminished OC and/or platelet function; 2) osteoblastic bone metastases will be decreased in the beta3-/- mice as a result of osteoclast and platelet dysfunction. Thus our specific aims are: 1) Determine the roles of defective osteoclasts and defective platelets in inhibiting osteolytic bone metastases. 2) Determine the roles of defective osteoclasts and defective platelets upon the development of osteoblastic bone metastases. Bone metastases will be established in beta3-/- mice and the osteoclast defective src-/- mice and the platelet defective DiYF mice by left cardiac ventricle (LV) and intra-tibial (IT) injection of osteolytic and osteoblastic cells lines. Bone metastases will be monitored by x-ray, 18-fluorodeexyglucose (18-FDG) PET scanning of in vivo tumor activity, and histomorphometry. Inhibitors of osteoclast alpha v beta3 and alphaIIbeta3 platelet specific inhibitors will be used in the osteolytic and osteoblastic LV and IT, bone metastasis assays. These studies will define whether beta3 function on host osteoclasts and platelets facilitate osteolytic and osteoblastic metastases and whether therapeutic inhibition of OC and/or beta3 function has a role in preventing or ameliorating skeletal metastases. These findings will direct future studies to define the molecular role of beta3 integrin subunit in the development of skeletal metastases.
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