Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

RBP-J 调节破骨细胞生成和关节炎骨吸收

• 批准号: 8819226
• 负责人: Baohong Zhao
• 金额: $ 24.9万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819226
• 关键词: Animal Model; Animals; Applied Genetics; Arthritis; Attenuated; Automobile Driving; Bone Development; Bone Resorption; Bone remodeling; Cells; Data; Development; Disease; Elements; Epigenetic Process; Equilibrium; FOS gene; Family; Feedback; Gene Expression; Generations; Genetic Transcription; Goals; Homeostasis; IFN consensus sequence binding protein; ITAM; In Vitro; Inflammatory; Integrins; Knowledge; Lead; Link; Macrophage Colony-Stimulating Factor; Mediating; Mediation; Modeling; Molecular; Musculoskeletal; Osteoclasts; Osteogenesis; Osteolysis; Pathogenesis; Pathologic; Pathway interactions; Periodontitis; Phase; Physiological; Play; Prosthesis; Psoriatic Arthritis; Regulation; Research; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; System; TNF gene; TNFSF11 gene; Testing; Tissues; Transcription Repressor/Corepressor; Transcriptional Regulation; bone; bone loss; cell type; chromatin modification; chromatin remodeling; cytokine; genetic variant; in vivo; inflammatory bone resorption; insight; interest; loss of function; macrophage; monocyte; notch protein; novel therapeutic intervention; osteoclastogenesis; pathologic bone resorption; prevent; promoter; receptor; response; therapeutic target; transcription factor

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.

通过RBP-J调节破骨细胞生成和关节骨骨分辨率 源自单核细胞/巨噬细胞前体的破骨细胞是独家骨吸收细胞 这种不仅在物理骨骼发育和重塑中起着重要作用，而且还起作用 积极作为一个关键的致病细胞，导致肌肉骨骼组织损伤和加速的发病机理 以炎症性骨溶解为特征的疾病，包括类风湿关节炎（RA），银屑病关节炎， 牙周炎和螺旋周期松动。该应用将重点放在约束的机制上 在炎症环境中，过度的破骨细胞生成和关节骨骨分辨率。破骨细胞生成是 由正面和负调节机制精致控制。与广泛研究 破骨细胞生成的阳性调节，反馈抑制性机制，负调节 破骨细胞的形成和功能的大小，尤其是在病理条件下，较少 感谢。这些机制的增强代表了抑制多余的潜在方法 破骨细胞生成和骨骼分辨率。候选人的长期目标是识别和理解 破骨细胞生成期间的稳态和反馈抑制机制，并利用这些知识 开发与炎症性溶解有关的疾病的新治疗方法。 候选人在TNF-介导的破骨细胞发生和骨破坏中特别有趣 因为TNF- - 是驱动炎症骨骼的关键致病因素。因此，候选人 已经开始研究以确定限制TNF-诱导的破骨细胞分化和 骨骼分辨率。候选人最近确定了被激活的转录因子RBP-J TNF-刺激和大大抑制了TNF-诱导的破骨细胞生成和骨骼分辨率 体外和体内，但对物理骨重塑的影响很小。这表明RBP-J是关键 炎症/病理骨骼的负调节剂，因此是有吸引力的治疗靶标的 与骨骼破坏有关的关节炎，例如RA。拟议研究的目标是：1）揭示 RBP-J负调节TNF-诱导的破骨细胞发生的分子机制，包括 RBP-J和 2）确定RBP-J在炎症性关节骨分辨率中的作用，包括 RBP-J的治疗靶向抑制关节炎动物模型中的炎症性骨恢复。这 候选人预计拟议的研究将洞悉限制病理学的机制 破骨细胞生成和炎性骨溶解，将在开发新疗法方面有用 在RA中发生的炎症环境中抑制骨骼分辨率的方法。