Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

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/巨噬细胞前体，是唯一的骨吸收细胞。 不仅在生理性骨骼发育和重塑中发挥重要作用，而且在功能 积极作为关键致病细胞导致肌肉骨骼组织损伤，加速发病 以炎性骨溶解为特征的疾病，包括类风湿性关节炎(RA)、牛皮癣关节炎、 牙周炎和假体周围松动。这个应用程序将集中在限制 炎症性环境中过度的破骨细胞生成和关节炎骨吸收。破骨细胞的形成是 受到正反两种监管机制的微妙控制。与广泛的研究形成对比的是 破骨细胞生成的正向调节，负向调节的反馈抑制机制 破骨细胞的形成和功能的大小，特别是在病理条件下，较少。 感激不尽。加强这些机制代表了抑制过度行为的潜在途径 破骨细胞生成和骨吸收。候选人的长期目标是识别和理解 破骨细胞形成过程中的动态平衡和反馈抑制机制，并利用这一知识在 炎症性骨溶解相关疾病的新治疗方法的发展。 候选人对肿瘤坏死因子介导的破骨细胞生成和骨破坏特别感兴趣 因为肿瘤坏死因子是导致炎症性骨吸收的关键致病因子。因此，候选人 已开始研究以确定抑制肿瘤坏死因子-1诱导的破骨细胞分化的机制和 骨吸收。候选人最近发现了转录因子RBP-J，该转录因子由 刺激并显著抑制肿瘤坏死因子诱导的破骨细胞生成和骨吸收 体外和体内，但对生理性骨重建的影响很小。这表明RBP-J是一个密钥 炎症性/病理性骨吸收的负调节因子，因此是有吸引力的治疗靶点 与骨质破坏相关的关节炎，如类风湿性关节炎。拟议研究的目标是：1)揭示 RBP-J负性调节肿瘤坏死因子诱导的破骨细胞生成的分子机制包括 NFATc1的转录调控和RBP-J对转录抑制物网络的调节，以及 2)明确RBP-J在炎症性关节炎骨吸收中的作用，包括其在骨吸收中的意义。 RBP-J靶向抑制关节炎动物模型的炎症性骨吸收。这个 候选人预计，拟议的研究将对抑制病理变化的机制有深入的了解。 破骨细胞生成和炎性骨溶解，将有助于开发新的治疗方法 在炎症环境中抑制骨吸收的方法，例如在RA中发生。

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 and 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-¿ mediated osteoclastogenesis and bone destruction because TNF-¿ is a key pathogenic factor driving inflammatory bone resorption. Therefore, the candidate has initiated studies to identify the mechanisms that restrain TNF-¿-induced osteoclast differentiation and bone resorption. The candidate has recently identified the transcription factor RBP-J that is activated by TNF-¿ stimulation and dramatically suppresses TNF-¿-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-¿ 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.