Mechanisms of AVB3 Integrin Mediated Bone Resorption

描述(申请人提供)：根据我们和其他人的观察，αvβ3整合素是目前治疗骨质疏松症和炎症性骨溶解等疾病的抗吸收靶点。从一开始，这项资助的目的就是通过表征整合素的相关分子和它们传递的骨降解信号，扩大整合素在治疗上的靶向潜力。除了那些抑制αvβ3的药物外，靶向信号分子的药物，如整合素的效应者c-src和syk，正在进行溶骨性疾病的临床试验，这一事实突显了这项研究的成功。在过去的筹资期间，我们实现了我们的具体目标。虽然我们继续努力定义αvβ3调节OC的机制，特别是在组织其细胞骨架的衍生信号的背景下，但我们目前的注意力转向整合素本身。我们阐述了整合素呈现激活构象的机制，该构象允许整合素识别配体并传递其骨吸收信号。我们和其他人的研究结果表明，M-CSF在这方面发挥了核心作用。我们已经证实，αvCSF3和M-β在组织OC细胞骨架方面是相互协作的。然而，我们的数据表明，M-csf发挥细胞骨架作用的主要途径是促使其受体c-fms将细胞内信号传递到β3整合素亚单位的细胞质区域。这些信号反过来将整合素从其默认的静止状态转变为其激活的构象，从而允许配体识别和细胞骨架组织事件。我们的发现还表明，Talin通过与α3整合素细胞质结构域中的特定残基相互作用，激活OCβvβ3及其衍生的信号。因此，我们推测，1)与其受体c-fms连接的M-CSF传递细胞内信号，激活OCS中的αvβ3整合素；2)β3胞浆结构域中的Talin及其识别序列介导M-CSF诱导的OC细胞骨架的组织和功能；3)体内抑制αvβ3的激活，减少病理性骨吸收。因此，我们的具体目标是确定1)M-CSF与其受体c-fms相互作用的细胞内信号传递机制，从而激活OCS中的αvβ3整合素；2)β3整合素胞浆结构域中Talin及其识别序列在介导M-CSF诱导的OC细胞骨架组织和功能中的作用；3)体内抑制αvβ3激活对病理性骨吸收的影响。

DESCRIPTION (provided by applicant): Prompted by our observations and those of others, the αvβ3 integrin is a current therapeutic anti-resorptive target for diseases such as osteoporosis and inflammatory osteolysis. The purpose of this grant, from its inception, has been to expand the potential of therapeutically targeting the integrin by characterizing its associated molecules and the bone-degrading signals they transmit. The success of this exercise is underscored by the fact that in addition to those inhibiting αvβ3, drugs targeting signaling molecules, such as c-Src and Syk, which are effectors of the integrin, in OCs, are in clinical trial for osteolytic diseases. We have, in the past funding period, fulfilled our specific aims. While our efforts continue to define the mechanisms by which αvβ3 regulates the OC, particularly in the context of derivative signals which organize its cytoskeleton, our current attention turns to the integrin, itself. We address the mechanisms by which the integrin assumes an activated conformation which permits it to recognize ligand and transmit its bone-resorptive signals. Our findings and those of others, indicate M-CSF plays a central role in this regard. We have established that αvβ3 and M-CSF collaborate in organizing the OC cytoskeleton. Our data indicate, however, that the principal means by which M-CSF exerts its cytoskeletal effect is to prompt its receptor c-Fms to transmit intracellular signals to the cytoplasmic domain of the β3 integrin subunit. These signals, in turn, transit the integrin from its default, resting state, to its activated conformation, permitting ligand recognition and cytoskeleton-organizing events. Our findings also suggest that talin activates OC αvβ3 and the signals derived thereof, by interacting with specific residues in the β3 integrin cytoplasmic domain. We hypothesize, therefore that 1) M-CSF, liganding its receptor, c-Fms, transmits intracellular signals which activate the αvβ3 integrin in OCs; 2) talin and its recognition sequences in the β3 cyoplasmic domain mediate M-CSF-induced OC cytoskeletal organization and function and 3) inhibiting αvβ3 activation, in vivo, diminishes pathological bone resorption. Our specific aims are therefore to determine 1) the mechanism by which M-CSF, interacting with its receptor c-Fms, transmits intracellular signals which activate the αvβ3 integrin in OCs; 2) the role of talin and its recognition sequences in the β3 integrin cytoplasmic domain in mediating M-CSF-induced OC cytoskeletal organization and function and 3) the impact of inhibiting αvβ3 activation, in vivo, on pathological bone resorption.