The role of myostatin in joint destruction in rheumatoid arthritis

肌生长抑制素（GDF-8）是转化生长因子（TGF-β）家族的成员，在骨骼肌中表达，并作为肌肉生长的负调节因子。最近的研究结果表明，肌生长抑制素也可能在调节骨发育中起作用，并且抑制肌生长抑制素可以减少骨吸收并改善骨形成。基于自身的初步结果，证明了肌肉生长抑制素在慢性破坏性关节炎中的疾病特异性表达以及对RANKL诱导的破骨细胞生成的增强作用，我们想研究肌肉生长抑制素是否在RA的发病机制中发挥作用。特别是，我们希望遵循这样的假设，即肌生长抑制素在关节炎关节中的表达与破骨细胞形成的增强有关，因此，在慢性炎性关节炎期间显著参与骨破坏。为此目的，我们将Mstn敲除小鼠与hTNFtg小鼠杂交，hTNFtg小鼠发展为TNF-α依赖性关节炎，并通过形态学、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）。进一步的实验信号转导通路参与myostatin促进破骨细胞的形成，以及在myostatin本身的调节将提供抑制这种强大的破骨细胞生成因子的起点。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RA的新治疗策略的发展。

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.