Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

描述（申请人提供）：RBP-J对破骨细胞生成和关节炎性骨吸收的调节.破骨细胞来源于单核细胞/巨噬细胞前体，是唯一的骨吸收细胞，不仅在生理性骨发育和重塑中发挥重要作用，而且作为导致肌肉骨骼组织损伤和加速以炎性骨质溶解为特征的疾病发病机制的关键致病细胞发挥积极作用，包括类风湿性关节炎（RA）、银屑病关节炎、牙周炎和假体周围松动。本申请将集中在抑制过度破骨细胞生成和关节炎性骨吸收的炎症设置的机制。破骨细胞的生成受到正负调控机制的微妙控制。与破骨细胞生成的正调控的广泛研究相反，负调控破骨细胞形成和功能的大小的反馈抑制机制，特别是在病理条件下，不太受欢迎。这些机制的增强代表了抑制过度破骨细胞生成和骨吸收的潜在方法。候选人的长期目标是识别和理解破骨细胞生成过程中的稳态和反馈抑制机制，并利用这些知识开发与炎症性骨质溶解相关疾病的新治疗方法。 该候选人对TNF-1介导的破骨细胞生成和骨破坏特别感兴趣，因为TNF-1是驱动炎性骨吸收的关键致病因子。因此，该候选人已启动研究，以确定抑制TNF-1诱导的破骨细胞分化和骨吸收的机制。该候选人最近鉴定了转录因子RBP-J，其被TNF-1刺激激活并在体外和体内显著抑制TNF-1诱导的破骨细胞生成和骨吸收，但对生理性骨重塑的影响极小。这表明RBP-J是炎性/病理性骨吸收的关键负调节剂，因此是与骨破坏相关的关节炎（如RA）的有吸引力的治疗靶点。拟议研究的目标是：1）揭示RBP-J负调节TNF-1诱导的破骨细胞生成的分子机制，包括NFATc 1的转录调节和RBP-J对转录阻遏物网络的介导，和2）鉴定RBP-J在炎性关节炎性骨吸收中的作用，包括RBP-J治疗靶向抑制关节炎动物模型中炎性骨吸收的重要性。候选人预计，拟议的研究将深入了解抑制病理性破骨细胞生成和炎性骨质溶解的机制，并将有助于开发新的治疗方法来抑制炎症环境中的骨吸收，如RA。

DESCRIPTION (provided by applicant): Regulation of osteoclastogenesis and arthritic bone resorption by RBP-J. Osteoclasts, derived from monocyte/macrophage precursors, are the exclusive bone resorptive cells that play an important role not only in physiological bone development and remodeling, but also function actively as a key pathogenic cell leading to musculoskeletal tissue damage and accelerating pathogenesis of diseases characterized by inflammatory osteolysis, including rheumatoid arthritis (RA), psoriatic arthritis, periodontitis an peri-prosthetic loosening. This application will focus on the mechanisms that restrain excessive osteoclastogenesis and arthritic bone resorption in inflammatory settings. Osteoclastogenesis is delicately controlled by positive and negative regulatory mechanisms. In contrast to the extensive study of the positive regulation of osteoclastogenesis, the feedback inhibitory mechanisms that negatively regulate the magnitude of osteoclast formation and function, especially in pathological conditions, are less appreciated. Augmentation of these mechanisms represents potential approaches to inhibiting excessive osteoclastogensis and bone resorption. The candidate's long term goals are to identify and understand the homeostatic and feedback inhibitory mechanisms during osteoclastogenesis, and to utilize this knowledge in the development of new therapeutic approaches to diseases associated with inflammatory osteolysis. The candidate is particularly interested in TNF-1 mediated osteoclastogenesis and bone destruction because TNF-1 is a key pathogenic factor driving inflammatory bone resorption. Therefore, the candidate has initiated studies to identify the mechanisms that restrain TNF-1-induced osteoclast differentiation and bone resorption. The candidate has recently identified the transcription factor RBP-J that is activated by TNF-1 stimulation and dramatically suppresses TNF-1-induced osteoclastogenesis and bone resorption in vitro and in vivo but has minimal effects on physiological bone remodeling. This indicates that RBP-J is a key negative regulator of inflammatory/pathologic bone resorption and thus an attractive therapeutic target for arthritis associated with bone destruction, such as RA. The goals of the proposed research are: 1) to reveal molecular mechanisms by which RBP-J negatively regulates TNF-1 induced osteoclastogenesis, including the transcriptional regulation of NFATc1 and mediation of the transcriptional repressor network by RBP-J, and 2) to identify the role of RBP-J in inflammatory arthritic bone resorption, including the significance of therapeutic targeting of RBP-J to suppress inflammatory bone resorption in arthritis animal models. The candidate anticipates that the proposed studies will yield insight into mechanisms that restrain pathologic osteoclastogenesis and inflammatory osteolysis, and will be useful in developing new therapeutic approaches to suppressing bone resorption in inflammatory settings such as occurs in RA.