Role of Beta 3 Integrin in Skeletal Metastasis

描述(由申请人提供)：乳腺癌和前列腺癌的骨转移是导致严重发病率和死亡率的原因。建立骨转移的机制尚不清楚。抑制破骨细胞(OC)功能的药物(即双膦酸盐)可以改善溶骨性和成骨转移性骨疾病，提示OCS参与了这两种形式的骨转移的发病机制。研究OCS在骨转移中的作用的一种方法是使用缺乏整合素亚单位Beta3的小鼠。我们有初步数据表明，在Beta3-/-小鼠中，溶骨性骨转移显著减少。β3/-小鼠存在两个基本缺陷：由α-vβ3介导的破骨细胞吸收减少和由αIIβ3介导的血小板聚集减少，这两者可能在骨转移的建立中起作用。通过β3整合素阻断血小板/肿瘤的相互作用可减少小鼠的肺转移，提示血小板β3整合素在转移中的作用。鉴于上述事实，我们假设1)由于OC和/或血小板功能降低，β3/-鼠的溶骨性转移减少；2)由于破骨细胞和血小板功能障碍，β3/-鼠的成骨细胞性骨转移减少。因此，我们的具体目标是：1)确定缺陷破骨细胞和缺陷血小板在抑制溶骨性骨转移中的作用。2)确定破骨细胞缺陷和血小板缺陷在成骨细胞性骨转移中的作用。在Beta3-/-小鼠、破骨细胞缺陷的src-/-小鼠和血小板缺陷的DiYF小鼠中，将通过左心(LV)和胫骨(IT)注射溶骨和成骨细胞系来建立骨转移。将通过X射线、18-氟代脱氧葡萄糖(18-FDG)体内肿瘤活性的PET扫描和组织形态计量学来监测骨转移。破骨细胞αvβ3和αIIbeta3的抑制物将用于溶骨性和成骨细胞性LV和IT的骨转移检测。这些研究将确定宿主破骨细胞和血小板上的Beta3功能是否促进溶骨和成骨转移，以及治疗抑制OC和/或Beta3功能是否具有预防或改善骨转移的作用。这些发现将指导未来的研究，以确定β3整合素亚单位在骨转移发生中的分子作用。

DESCRIPTION (provided by applicant): 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.