Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

描述（由申请人提供）：RBP-J对破骨细胞生成和关节炎骨吸收的调节作用。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，不仅在骨的生理发育和重塑中发挥重要作用，而且是导致肌肉骨骼组织损伤和加速炎症性骨溶解疾病发病的关键致病细胞，包括类风湿关节炎（RA）、银屑病关节炎、牙周炎和假体周围松动。本应用将集中于炎症环境下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正、负调控机制的微妙控制。与对破骨细胞形成的正调控的广泛研究相反，对破骨细胞形成和功能的负调控的反馈抑制机制，特别是在病理条件下，很少被认识到。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确定和了解破骨细胞发生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介导的破骨细胞发生和骨破坏特别感兴趣，因为TNF-1是驱动炎症性骨吸收的关键致病因子。因此，候选人已经开始研究抑制tnf -1诱导的破骨细胞分化和骨吸收的机制。该候选人最近发现了转录因子RBP-J，该因子可被TNF-1刺激激活，并在体外和体内显著抑制TNF-1诱导的破骨细胞发生和骨吸收，但对生理性骨重塑的影响很小。这表明RBP-J是炎症/病理性骨吸收的关键负调节因子，因此是关节炎相关骨破坏的一个有吸引力的治疗靶点，如类风湿性关节炎。拟开展的研究目标是：1)揭示RBP-J负调控TNF-1诱导的破骨细胞发生的分子机制，包括RBP-J对NFATc1的转录调控和转录抑制因子网络的介导作用；2)确定RBP-J在炎性关节炎骨吸收中的作用，包括在关节炎动物模型中靶向治疗抑制炎性骨吸收的意义。该候选人预计，拟议的研究将深入了解抑制病理性破骨细胞发生和炎症性骨溶解的机制，并将有助于开发新的治疗方法，以抑制关节炎等炎症环境下的骨吸收。

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.