Mechanisms of AVB3 Integrin Mediated Bone Resorption

描述（由申请人提供）：通过我们的观察和其他人的观察证实，α v β 3整联蛋白是目前用于诸如骨质疏松症和炎性骨质溶解的疾病的治疗性抗再吸收靶标。这项资助的目的，从一开始，就通过表征其相关分子和它们传递的骨降解信号来扩大治疗靶向整合素的潜力。这项工作的成功是由以下事实强调的，即除了那些抑制α v β 3的药物外，靶向信号分子的药物，如c-Src和Syk，它们是OC中整联蛋白的效应物，正在进行溶骨性疾病的临床试验。 在过去的资助期间，我们实现了我们的具体目标。虽然我们的努力继续定义的机制，通过它av 3调节OC，特别是在组织其细胞骨架的衍生信号的背景下，我们目前的注意力转向整合素本身。我们解决的机制，整合素假设活化构象，使其能够识别配体和传递其骨吸收信号。我们的研究结果和其他人的研究结果表明，M-CSF在这方面起着核心作用。 我们已经确定，α v β 3和M-CSF合作组织OC细胞骨架。然而，我们的数据表明，M-CSF发挥其细胞骨架作用的主要手段是促使其受体c-Fms将细胞内信号传递到整合素3亚基的胞质结构域。这些信号反过来又将整合素从其默认的静息状态转变为其活化构象，从而允许配体识别和细胞因子组织事件。我们的研究结果还表明，talin激活OC av 3及其衍生的信号，通过与特定的残基在3整合素胞质结构域的相互作用。因此，我们假设：1）M-CSF与其受体c-Fms结合，传递细胞内信号，激活OC中的α v β 3整联蛋白; 2）α v β 3胞质结构域中的talin及其识别序列介导M-CSF诱导的OC细胞骨架组织和功能; 3）抑制α v β 3激活，在体内减少病理性骨吸收。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，传递激活OC中α v β 3整合素的细胞内信号的机制; 2）talin及其在α v β 3整合素胞质结构域中的识别序列在介导M-CSF诱导的OC细胞骨架组织和功能中的作用; 3）抑制α v β 3整合素的影响。3激活，在体内，对病理性骨吸收。 公共卫生相关性：大多数有骨质疏松性骨折风险的患者接受双膦酸盐治疗，这与并发症（如非典型骨折）的相关性越来越高。目前的资助，从一开始，就专注于为这些患者发现新的治疗靶点，特别是针对分子，称为整合素，介导骨吸收细胞附着到骨骼基质。我们的努力取得了成功，这一事实突出表明，整合素靶向药物正在临床试验中治疗骨质疏松症。

DESCRIPTION (provided by applicant): Prompted by our observations and those of others, the av¿3 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 av¿3, 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 av¿3 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 av¿3 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 ¿3 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 av¿3 and the signals derived thereof, by interacting with specific residues in the ¿3 integrin cytoplasmic domain. We hypothesize, therefore that 1) M-CSF, liganding its receptor, c-Fms, transmits intracellular signals which activate the av¿3 integrin in OCs; 2) talin and its recognition sequences in the ¿3 cyoplasmic domain mediate M-CSF-induced OC cytoskeletal organization and function and 3) inhibiting av¿3 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 av¿3 integrin in OCs; 2) the role of talin and its recognition sequences in the ¿3 integrin cytoplasmic domain in mediating M-CSF-induced OC cytoskeletal organization and function and 3) the impact of inhibiting av¿3 activation, in vivo, on pathological bone resorption. PUBLIC HEALTH RELEVANCE: Most patients at risk for osteoporotic fractures are treated with bisphosphonates, which are increasingly associated with complications such as atypical fractures. The present grant, from its inception, has focused on discovering new therapeutic targets for these patients, specifically addressing molecules, known as integrins, which mediate the attachment of bone resorbing cells to skeletal matrix. The success of our efforts is underscored by the fact that integrin-targeting drugs are in clinical trial for the treatment of osteoporosis.