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: 9906762
• 负责人: Baohong Zhao
• 金额: $ 38.72万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906762
• 关键词: Animal Model; Arthritis; Attention; Automobile Driving; Bone Development; Bone Resorption; Bone remodeling; Cells; Development; Disease; Down-Regulation; FOXO3A gene; Family member; Feedback; Genetic; Goals; Grant; High-Throughput Nucleotide Sequencing; IFN consensus sequence binding protein; ITAM; Inflammatory; Integrins; Interferons; Knockout Mice; Knowledge; Macrophage Colony-Stimulating Factor; Mediating; MicroRNAs; Musculoskeletal; Osteoclasts; Osteolysis; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Periodontitis; Physiological; Physiological Processes; Play; Prosthesis Loosenings; Psoriatic Arthritis; Regulation; Rheumatoid Arthritis; Role; Signal Transduction; System; TNF gene; TNFSF11 gene; Therapeutic; Tissues; Transgenic Mice; Treatment Efficacy; Virulence Factors; autocrine; bone; bone erosion; bone loss; cytokine; gain of function; genetic approach; genome-wide; in vivo; inflammatory bone resorption; insight; macrophage; miRNA expression profiling; monocyte; novel; novel therapeutic intervention; osteoclastogenesis; pathologic bone resorption; prevent; receptor; transcription factor

Regulation of osteoclastogenesis and arthritic bone resorption by RBP-J Osteoclasts play an important role not only in physiological bone development and remodeling, but also function actively as key pathogenic cells 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. In contrast to the extensive study of the positive regulation of osteoclastogenesis, the feedback inhibitory mechanisms that negatively regulate the magnitude of osteoclastogenesis and bone resorption, especially in pathological conditions, are little appreciated. Our long term goals are to identify and understand the inhibitory mechanisms and to utilize this knowledge in development of new therapeutic approaches to diseases associated with inflammatory osteolysis. Using miRNA-seq, we have obtained the genome-wide profile of miRNA expression induced by TNF-in osteoclast precursors. We furthermore identified miR-182 as a novel miRNA that drastically promotes inflammatory osteoclastogenesis driven by TNF- and whose expression is suppressed by RBP-J. In our previous project period supported by a K99/R00 grant, we demonstrated and established that RBP-J is a key negative regulator that predominantly restrains TNF-induced osteoclastogenesis and inflammatory bone resorption. Recently, we found that the RBP-J-regulated miR-182 promotes TNF- induced osteoclastogenesis via inhibition of Foxo3 and Maml1, two miR-182 direct targets. Thus, suppression of miR-182 by RBP-J may serve as an important mechanism that restrains TNF- induced osteoclastogenesis. Targeting of the newly described RBP-J-miR-182-Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone resorption. In this application, we will apply genetic approaches to further establish the role of the RBP-J-miR- 182-Foxo3/Maml1 axis in vivo and dissect underlying mechanisms. Specifically, we will 1) investigate the role of the RBP-J-miR-182 axis in vivo using genetic approaches; 2) investigate the mechanisms by which miR-182 target, Foxo3, regulates TNF- induced osteoclastogenesis, and the functional importance of this regulation in vivo. We anticipate that our studies will provide genetic evidence and yield insight into mechanisms that restrain pathologic osteoclastogenesis and inflammatory osteolysis, and will be useful in developing new therapeutic approaches for suppressing bone resorption in inflammatory settings.

通过RBP-J调节破骨细胞生成和关节骨骨分辨率 破骨细胞不仅在物理骨骼发育和重塑中起着重要作用，而且在 同样可以作为关键的致病细胞发挥作用，从而导致肌肉骨骼组织损伤和加速度 以炎性骨溶解为特征的疾病的发病机制，包括类风湿关节炎（RA）， 银屑病关节炎，牙周炎和杂扫松开。与广泛的研究相比 破骨细胞生成的阳性调节，反馈抑制性机制，这些机制对调节 破骨细胞生成和骨骼分辨率的大小，尤其是在病理条件下，很少 感谢。我们的长期目标是识别和理解抑制机制并利用 在开发与炎症有关的疾病的新治疗方法方面的知识 溶解性。使用miRNA-Seq，我们获得了由 tnf-在破骨细胞前体。我们此外，将miR-182识别为一种新颖的miRNA 促进由TNF-驱动的炎症破骨细胞发生，其表达被抑制 RBP-J。在我们以前的项目期间由K99/R00赠款支持，我们证明并建立了 RBP-J是一个关键的负调节剂 炎症骨骼分辨率。最近，我们发现RBP-J调节的miR-182促进了TNF- 通过抑制FOXO3和MAML1（两个miR-182直接靶标）诱导的破骨细胞生成。那， RBP-J抑制miR-182可能是限制TNF-诱导的重要机制 破骨细胞生成。新描述的RBP-J-MIR-182-FOXO3/MAML1轴的靶向可能代表 一种有效的治疗方法，可抑制炎症破骨细胞生成和骨骼分辨率。 在此应用中，我们将采用遗传方法来进一步确立RBP-J-MIR-的作用 182-FoxO3/MAML1轴体内并解剖潜在的机制。具体来说，我们将1）调查 使用遗传方法在体内RBP-J-MIR-182轴的作用； 2）研究的机制 miR-182靶标，FOXO3调节TNF-诱导的破骨细胞生成，并且功能重要性 体内调节。我们预计我们的研究将提供遗传证据，并对 限制病理破骨细胞生成和炎症性溶解的机制，将在 开发新的治疗方法来抑制炎症环境中的骨骼分辨率。