异基因MSC通过抑制myostatin调控破骨细胞分化治疗RA的机制研究

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by progressive joint destruction. Osteoclast differentiation and activation regulated by many factors paly a key role in RA bone destruction. Myostatin (MSTN) is a new member of the TGF-beta superfamily. The latest study has proved that MSTN is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in a mouse model of RA. Mesenchymal stem cells (MSC) are widely used in the treatment of autoimmune diseases for their immune modulatory effects. In previous study, we observed high expression of MSTN in synovial membranes of patients with RA and collagen induced arthritis (CIA) mice. Allogeneic MSC transplantation can inhibit osteoclast differentiation in CIA mice and MSTN expression were decreased significantly in synovial tissues after transplantation. Therefore, we hypothesized that regulating osteoclast differentiation by inhibiting MSTN expression might be one of the mechanisms for the effective treatment of RA with allogeneic MSC. In the current study, we will further investigate the regulation mechanism of MSTN on osteoclast differentiation and activation, inhibitory mechanism of allogeneic MSC on RA synovial fibroblast, thereby to deeply indicate the mechanisms by which allogeneic MSC treat RA effectively. The results will provide a new target and theoretical basis for the treatment of RA.

类风湿关节炎（RA）是以进行性关节破坏为特征的全身性自身免疫病，多种因子参与破骨细胞分化及活性调节是RA骨破坏的关键因素。Myostatin（MSTN）属TGF-β超家族新成员，最新研究发现MSTN对RA破骨细胞有直接调控作用，阻断MSTN可抑制RA模型鼠骨破坏。间充质干细胞（MSC）具有广泛免疫调节作用，已成为自身免疫病治疗有前途的细胞。我们前期研究发现RA患者和胶原诱导关节炎（CIA）小鼠关节滑膜高表达MSTN，异基因MSC移植可抑制CIA小鼠破骨分化，且移植后小鼠滑膜组织MSTN表达明显降低。因此，我们推测通过抑制MSTN表达调控破骨分化可能是异基因MSC有效治疗RA的机制之一。本项目将进一步研究MSTN对RA破骨细胞的调控机制，MSC抑制RA关节滑膜成纤维细胞MSTN表达的机制，从而揭示异基因MSC有效治疗RA的新机制，为RA治疗提供新的靶点及理论依据。

类风湿关节炎（RA）是一种以炎性骨侵蚀为特征的系统性自身免疫性疾病。RA炎症状态下，滑膜成纤维细胞（FLS）过度活化并分泌炎症因子，成骨细胞和破骨细胞之间的动态平衡被打破，破骨增强而导致骨关节破坏。本课题研究发现，RA患者滑膜中的MSTN表达显著高于骨关节炎（OA）对照组，并进一步发现，破骨前体细胞在MSTN刺激下，成熟的破骨细胞比例更高，骨吸收实验表明MSTN能够促进破骨细胞的骨吸收功能。为了进一步探讨MSTN对破骨细胞作用的机制，我们发现RA患者的FLS能够促进破骨前体细胞的破骨分化，通过siRNA干扰FLS的MSTN的表达后，RA的FLS促进破骨前体细胞分化的能力减弱，而OA患者的FLS细胞过表达MSTN后，能够促进破骨前体细胞的分化。但是MSTN对其受体的表达没有影响，MSTN结合其受体后通过NF-κB和Smad2通路影响促进破骨细胞NFATC1的表达。通过MSC治疗CIA小鼠发现，MSC能够缓解关节的骨损伤，通过体外研究发现，MSC可以分泌IL-10在抑制FLS对破骨细胞中发挥作用，抗IL-10的抗体可以减弱MSC抑制FLS的MSTN的表达。本研究结果有助于了解MSC移植治疗RA的疗效和机制，为临床推广应用MSC治疗RA及其他自身免疫病，进一步提高治疗效果提供依据。