The research of rheumatoid arthritis from aspect of developmental biology.

类风湿性关节炎（RA）是一种与关节疼痛相关的疾病，并威胁生活质量。类风湿性关节炎影响全球约1%的人口，但其具体的治疗方法尚未问世。我们最近成功克隆了E3泛素连接酶syno小提琴，并证明了该分子是关节病的致病因子之一。进一步提出了新的疾病概念；RA是一种与高内质网相关的退化疾病。通过进一步的分析，我们发现滑膜小提琴在基因靶向系统的胚胎发生中是必不可少的。滑膜鞘缺陷小鼠（syno^<-l->）显示胎儿肝细胞凋亡增强引起的贫血。即syno^<-1->胎儿肝脏对红细胞的护理活性存在缺陷。这种现象具有类风湿关节炎的对称性特征，即类风湿关节炎骨髓基质细胞具有护理细胞样活性，而类风湿关节炎是一种加速这种护理活性的疾病。因此，syno^<-1->的结果表明，胚胎发生与RA有密切的关系，并提示从相反的角度分析可能会开发出新的RA治疗方法；syno ^ < 1 - >。然而，滑膜小提琴在这些作用中的分子机制尚不清楚。为了澄清这些问题，我们分析了滑膜鞘空细胞的蛋白表达谱。在这里，我们报道滑膜小提琴靶向肿瘤抑制基因p53泛素化。滑膜小提琴在细胞质中隔离和代谢p53，负向调节其细胞水平和生物学功能，包括转录、细胞周期调节和凋亡。此外，滑膜小提琴的这些p53调控功能与其他E3泛素连接酶（如MDM2、Pirh2和Cop1）无关，它们形成了自调节反馈回路。我们的研究结果为滑膜小提琴介导的p53信号传导提供了新的见解。

Rheumatoid arthritis (RA) is a disease associated with painful joint, and threatens the quality of life. RA affects approximately 1% of the population worldwide, however its specific cure is not available yet. We recently succeeded cloning of Synoviolin, an E3 ubiquitin ligase, and proved this molecule is one of the causative factors for arthropathy. Furthermore, we proposed the new disease concept ; RA is a hyper endoplasmic reticulum associated degradation disease. From further analysis, we found that Synoviolin is essential for embryogenesis using gene targeting system. synoviolin deficient mice (syno^<-l->) showed that anemia caused by enhancement of apoptosis in fetal liver. Namely, syno^<-1-> fetal liver demonstrated the defect of nursing activity to erythrocyte. This phenomenon has a symmetrical feature of RA, that is, RA bone marrow stromal cells have nurse cell like activity, and RA is a disease which accelerated this nursing activity. Therefore, from the results of syno^<-1->, it becomes clear that embryogenesis and RA have close relation, and suggested that new cure of RA might be developed by analysis of quite an opposite aspect ; syno^<-1->.However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.