Investigation of the role of the nuclear receptor NR4a1 during bone turnover and maintenance of the hematopoietic niche in the bone marrow

研究核受体 NR4a1 在骨转换和维持骨髓造血生态位中的作用

• 批准号: 168901901
• 负责人: Professor Dr. Gerhard Krönke
• 金额: --
• 依托单位: Institut für Molekulare Endokrinologie der Tiere
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/168901901?language=en
• 关键词: Investigation; role; nuclear; receptor; NR4a1

Both metabolic and inflammatory disorders are accompanied by aggravated osteoporosis, which is characterized by a shifted balance between bone formation and bone resorption. Osteoclasts are key cellular players in the pathogenesis of osteoporosis since they mediate the process of increased bone resorption. Nuclear receptors are central regulators of fat and glucose metabolism. Moreover, they have been implicated in the modulation of the inflammatory response. Preliminary data of our groups show high expression of the nuclear receptor NR4A1 in cells of the monocytic lineage including macrophages and osteoclasts. Moreover these data indicate a dual role of this transcription factor both as regulator of bone metabolism and of inflammation. It is the aim of this project to further elucidate the role of NR4A1 in bone metabolism and inflammation in vivo and in vitro. We will study NR4A -/- mice and apply experimental models of postmenopausal osteoporosis (ovariectomy model), inflammatory osteoporosis (TNFα-transgenic mice) and mouse models of arthritis (TNFα- transgenic mouse model and K/BxN serum transfer). Using molecular approaches we will seek to identify target genes of the NR4A family of proteins and characterize their function in key cells such as macrophages, osteoclasts and osteoblasts. These experiments will help to understand the role of the NR4A family of nuclear receptors during chronic inflammatory disorders such as rheumatoid arthritis (RA) and during associated changes in bone metabolism, which will eventually lead to the identification of novel therapeutic targets for the treatment of these diseases.

代谢和炎症性疾病都伴随着骨质疏松症的加重，其特征在于骨形成和骨吸收之间的平衡改变。破骨细胞是骨质疏松症发病机制中的关键细胞参与者，因为它们介导骨吸收增加的过程。核受体是脂肪和葡萄糖代谢的中心调节器。此外，它们还涉及炎症反应的调节。我们小组的初步数据显示核受体NR 4A 1在单核细胞谱系的细胞中的高表达，包括巨噬细胞和破骨细胞。此外，这些数据表明该转录因子作为骨代谢和炎症的调节剂的双重作用。本项目的目的是进一步阐明NR 4A 1在体内和体外骨代谢和炎症中的作用。我们将以NR 4A-/-小鼠为研究对象，应用绝经后骨质疏松症（卵巢切除模型）、炎性骨质疏松症（TNF α转基因小鼠）和关节炎小鼠模型（TNFα转基因小鼠模型和K/BxN血清转移）的实验模型。利用分子生物学方法，我们将寻求确定NR 4A蛋白家族的靶基因，并表征其在关键细胞如巨噬细胞、破骨细胞和成骨细胞中的功能。这些实验将有助于了解NR 4A家族核受体在慢性炎症性疾病如类风湿性关节炎（RA）和骨代谢相关变化期间的作用，这最终将导致识别用于治疗这些疾病的新治疗靶点。