The role of myostatin in joint destruction in rheumatoid arthritis

肌生长抑制素在类风湿性关节炎关节破坏中的作用

• 批准号: 169271848
• 负责人: Dr. Berno Dankbar, Ph.D.
• 金额: --
• 依托单位: Institut für Muskuloskelettale Medizin
• 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/169271848?language=en
• 关键词: role; myostatin; joint; destruction; rheumatoid

Myostatin (GDF-8) is a member of the transforming growth factor-( (TGF-() family that is expressed in skeletal muscle and serves as a negative regulator of muscle growth. Recent findings indicate that myostatin may also play a role in regulating bone development and that inhibition of myostatin may diminish bone resorption and improve bone formation. Based on own preliminary results demonstrating a disease-specific expression of myostatin in chronic destructive arthritis and a potentiating effect on RANKL- induced osteoclastogenesis, we want to study whether myostatin plays a role in the pathogenesis of RA. In particular, we want to follow the hypothesis that the expression of myostatin in arthritic joints is associated with an enhanced osteoclast formation and thus, significantly involved in bone destruction during chronic inflammatory arthritis. For this purpose, we will cross the Mstn-knockout mice into hTNFtg mice that develop a TNF-alpha dependent arthritis and analyze the development and severity of disease (e.g. inflammation, synovial hyperplasia, bone erosion) by morphometric, histological and immunohistochemical methods. Further experiments on signal transduction pathways involved in the myostatinboosted osteoclast formation as well as in the regulation of myostatin itself will provide starting points for the inhibition of this potent osteoclastogenic factor. This project will provide new insights into the mechanisms of inflammatory bone destruction and facilitate the development of novel treatment strategies for chronic inflammatory disorders, particularly RA.

肌肉生长抑制素(GDF-8)是转化生长因子家族的一员，在骨骼肌中表达，是肌肉生长的负调控因子。最近的研究结果表明，myostatin也可能在骨发育中发挥作用，抑制myostatin可能会减少骨吸收，促进骨形成。基于自己的初步研究结果表明，在慢性破坏性关节炎中存在疾病特异性的Myostatin表达，并且对RANKL诱导的破骨细胞生成有促进作用，我们想要研究myostatin是否在RA的发病机制中起作用。特别是，我们想要遵循这样的假设，即在关节炎关节中肌肉抑制素的表达与增强的破骨细胞形成有关，因此，在慢性炎症性关节炎期间，肌肉生长抑制素显著参与骨破坏。为此，我们将MSTN基因敲除的小鼠转变为hTNFtg小鼠，发展成依赖肿瘤坏死因子的关节炎，并通过形态计量、组织学和免疫组织化学方法分析疾病的发展和严重程度(例如炎症、滑膜增生、骨侵蚀)。进一步研究肌抑素促进破骨细胞形成的信号转导途径，以及对其自身的调控，将为抑制这种强有力的破骨细胞因子提供起点。该项目将为炎症性骨破坏的机制提供新的见解，并促进慢性炎症性疾病，特别是类风湿关节炎的新治疗策略的发展。