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骨吸收的调节。破骨细胞来源于单核/巨噬细胞前体细胞，是唯一的骨吸收细胞，不仅在生理性骨发育和重建中发挥重要作用，而且是导致肌肉骨骼组织损伤和加速类风湿性关节炎、银屑病、牙周炎和假体周围松动等炎症性骨溶解疾病的关键致病细胞。这项应用将集中在炎症环境中抑制过度破骨细胞生成和关节炎骨吸收的机制。破骨细胞的发生受到积极和消极调节机制的微妙控制。与对破骨细胞生成的正向调节的广泛研究相比，负向调节破骨细胞形成和功能的反馈抑制机制，特别是在病理条件下，较少被认识。这些机制的加强代表了抑制过度的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了解破骨细胞形成过程中的动态平衡和反馈抑制机制，并利用这些知识开发与炎性骨溶解相关的疾病的新治疗方法。候选人对肿瘤坏死因子-1介导的破骨细胞形成和骨破坏特别感兴趣，因为肿瘤坏死因子-1是驱动炎症性骨吸收的关键致病因子。因此，候选人已经开始了研究，以确定抑制肿瘤坏死因子-1诱导的破骨细胞分化和骨吸收的机制。这位候选人最近发现了转录因子RBP-J，该转录因子可被肿瘤坏死因子-1激活，在体外和体内显着抑制肿瘤坏死因子-1诱导的破骨细胞形成和骨吸收，但对生理性骨重建的影响很小。这表明RBP-J是炎性/病理性骨吸收的关键负性调节因子，因此是治疗与骨破坏相关的关节炎(如RA)的有吸引力的靶点。本研究的目的是：1)揭示RBP-J负性调节肿瘤坏死因子-1诱导的破骨细胞生成的分子机制，包括RBP-J对NFATc1的转录调控和RBP-J对转录抑制物网络的调节；2)确定RBP-J在炎性关节炎骨吸收中的作用，包括RBP-J靶向抑制关节炎动物模型中炎性骨吸收的意义。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溶解的机制，并将有助于开发新的治疗方法，以抑制炎症环境中的骨吸收，如在RA中发生的。

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.