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.

RBP-J对破骨细胞生成和关节炎性骨吸收的调节作用 破骨细胞不仅在生理性骨发育和骨重建中起重要作用， 还作为导致肌肉骨骼组织损伤和加速 以炎性骨质溶解为特征的疾病的发病机制，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。与广泛的研究相比， 破骨细胞生成的正调节，负调节破骨细胞生成的反馈抑制机制， 破骨细胞生成和骨吸收的程度很小，尤其是在病理条件下 赞赏.我们的长期目标是识别和理解抑制机制， 这种知识在开发新的治疗方法，以疾病相关的炎症 骨质溶解使用miRNA-seq，我们已经获得了全基因组范围内的miRNA表达谱， 破骨细胞前体中的TNF-α。我们进一步鉴定了miR-182作为一种新的miRNA， 促进由TNF-α驱动的炎性破骨细胞生成，其表达被 RBP-J。在我们上一个项目期间由K99/R 00赠款支持，我们展示并建立了 RBP-J是主要抑制TNF-α诱导的破骨细胞生成的关键负调节因子， 炎性骨吸收最近，我们发现RBP-J调控的miR-182促进TNF-α表达， 通过抑制Foxo 3和Maml 1（两个miR-182直接靶点）诱导破骨细胞生成。因此，在本发明中， RBP-J抑制miR-182可能是抑制TNF-α诱导的miR-182表达的重要机制。 破骨细胞生成新描述的RBP-J-miR-182-Foxo 3/Maml 1轴的靶向可能代表 抑制炎性破骨细胞生成和骨吸收的有效治疗方法。 在本申请中，我们将应用遗传学方法来进一步确定RBP-J-miR-21的作用。 182-Foxo 3/Maml 1轴在体内和解剖的潜在机制。具体来说，我们将1）调查 使用遗传方法研究RBP-J-miR-182轴在体内的作用; 2）研究RBP-J-miR-182轴在体内的作用机制， miR-182靶点Foxo 3调节TNF-α诱导的破骨细胞生成， 体内调节。我们预计，我们的研究将提供遗传证据，并深入了解 抑制病理性破骨细胞生成和炎症性骨质溶解的机制，并将用于 开发抑制炎症环境中骨吸收的新治疗方法。