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: 8827675
• 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/8827675
• 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; 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 erosion; bone loss; cell type; chromatin modification; chromatin remodeling; cytokine; genetic approach; 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.

RBP-J对破骨细胞生成和关节炎性骨吸收的调节作用 破骨细胞来源于单核/巨噬细胞的前体细胞，是唯一的骨吸收细胞 不仅在生理性骨发育和重塑中起重要作用， 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发病机制， 以炎性骨质溶解为特征的疾病，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。本应用程序将集中在抑制机制， 在炎症环境中过度的破骨细胞生成和关节炎性骨吸收。破骨细胞生成是 受到积极和消极调节机制的微妙控制。与广泛的研究相比， 破骨细胞生成的正调节，负调节的反馈抑制机制， 破骨细胞形成和功能，特别是在病理条件下， 赞赏.这些机制的增强代表了抑制过度免疫的潜在方法。 破骨细胞生成和骨吸收。候选人的长期目标是识别和理解 破骨细胞生成过程中的稳态和反馈抑制机制，并利用这一知识， 与炎性骨质溶解相关疾病的新治疗方法的开发。 候选人对TNF-α介导的破骨细胞生成和骨破坏特别感兴趣 因为TNF-α是驱动炎性骨吸收的关键致病因子。因此，候选人 已经启动了研究，以确定抑制TNF-α诱导的破骨细胞分化的机制， 骨吸收候选人最近已经确定了转录因子RBP-J，它被激活， TNF-α刺激并显著抑制TNF-α诱导的破骨细胞生成和骨吸收， 但对生理性骨重塑的影响最小。这表明RBP-J是一个关键 炎性/病理性骨吸收的负调节剂，因此是一个有吸引力的治疗靶点， 与骨破坏相关的关节炎，如RA。本研究的目的是：1）揭示 RBP-J负调节TNF-α诱导的破骨细胞生成的分子机制，包括 RBP-J对NFATc 1的转录调节和转录抑制因子网络的介导，以及 2)确定RBP-J在炎性关节炎骨吸收中的作用，包括 RBP-J治疗靶向抑制关节炎动物模型中的炎性骨吸收。的 候选人预计，拟议的研究将产生深入了解机制，抑制病理 破骨细胞生成和炎性骨质溶解，并将有助于开发新的治疗 在炎症环境中抑制骨吸收的方法，例如在RA中发生的方法。