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 破骨细胞不仅在生理性骨发育和重建中发挥重要作用，而且 也积极发挥关键致病细胞的作用，导致肌肉骨骼组织损伤和加速 以炎性骨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， 破骨细胞生成的正向调节，负向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，特别是在病理条件下。 感激不尽。我们的长期目标是识别和理解抑制机制，并利用 在开发与炎症性疾病相关的新治疗方法方面的知识 骨溶解。使用miRNA-seq，我们已经获得了诱导miRNA表达的全基因组图谱 破骨细胞前体细胞表达肿瘤坏死因子-。我们进一步鉴定了miR-182是一种新的miRNA，它极大地 促进肿瘤坏死因子-驱动的炎症性破骨细胞生成并抑制其表达 RBP-J。在我们之前的项目期间，在K99/R00赠款的支持下，我们演示并建立了 RBP-J是一种关键的负性调节因子，主要抑制肿瘤坏死因子-诱导的破骨细胞生成，并 炎症性骨吸收。最近，我们发现RBP-J调节的miR-182促进肿瘤坏死因子- 通过抑制两个miR-182直接靶点Foxo3和Maml1诱导破骨细胞的形成。因此， RBP-J抑制miR182可能是抑制肿瘤坏死因子-诱导的重要机制 破骨细胞生成。靶向新描述的RBP-J-miR-182-Foxo3/Maml1轴可能代表 抑制炎症性破骨细胞生成和骨吸收的有效治疗方法。 在这一应用中，我们将应用遗传学方法进一步确定RBP-J-miR- 182-Foxo3/Maml1轴在体内的表达，并剖析其可能的机制。具体地说，我们将1)调查 用遗传学方法研究RBP-J-miR-182轴在体内的作用；2)研究 MIR-182靶基因Foxo3调节肿瘤坏死因子-诱导的破骨细胞生成及其功能重要性 体内调节。我们预计，我们的研究将提供遗传证据，并获得对 抑制病理性破骨细胞生成和炎性骨溶解的机制，并将在 开发新的治疗方法，以抑制炎症环境中的骨吸收。

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.