Novel Synovial Role in Pathogenesis of Gout

摘要 痛风是一种高度流行的疾病，最常见的表现为急性发作性滑膜炎， 通常是极度痛苦的痛风作为一个公共卫生问题继续增长。述病症是 尿酸的升高会促进关节炎的发生，而关节炎的临床表型是由 与尿酸盐结晶的关节沉积物相关的炎症反应。然而，痛风的发展只有在一个 高尿酸血症受试者的少数子集。此外，对沉积的尿酸盐晶体的临床反应是高度敏感的。 变量，包括急性关节炎的频率和程度，以及进展为可触及的皮下痛风石， 慢性关节炎和侵蚀性关节损伤。定义新的治疗靶点和生物标志物的需求尚未得到满足 痛风发作并发展为侵蚀性关节疾病这种高风险/高回报的理由 应用是，通过澄清在这些领域的知识的主要差距，工作将是范式转移， 潜在地确定新的目标，以帮助预防和限制痛风相关的发病率。新发现，包括 表明细胞外基质O-连接糖蛋白的改变 成分，如粘蛋白型边界润滑剂润滑，和活性尿酸泵入关节， 在痛风发生中起作用的转运机制尚未确定。我们的科学前提是，在滑膜中， 成纤维细胞衬里细胞（FLS），润滑素和其他粘蛋白型细胞外蛋白的机械相关变化 基质O-糖蛋白和增加的尿酸盐分泌处于促进“普通痛风”的机制性LOP中， 并发展为慢性破坏性滑膜炎我们将主要使用组合的候选基因和反向 遗传学的方法来分析一个非常不寻常的观察，特别是痛风的情况下，作为一个“实验， 自然”。先证者是一名健康女性，没有高尿酸血症，22岁时出现破坏性的 髋关节滑膜炎，小关节和中关节不对称急性痛风性关节炎发作，伴典型趾关节 痛风糜烂，痛风已确诊收集先证者全基因组DNA的初步数据， 血清糖组学、蛋白质组学和糖蛋白组学提示润滑素生物合成失调， 其他粘蛋白型O-糖蛋白，通常作为炎症的组成性抑制剂。基因 候选物在TMEM 171的“反应组”中高度富集，TMEM 171是一种不完全表征的跨膜蛋白， 一种与尿酸盐转运有关的分子，最近被定义为痛风易感基因。具体而言是 TMEM 171反应组包含超过20种参与糖蛋白生物合成的分子，超过10种参与糖蛋白生物合成的分子。 粘蛋白型。O-糖蛋白和超过20个ADAMTS蛋白酶超家族成员。这项工作旨在阐明 滑膜细胞外基质生物学、尿酸盐代谢和转运、痛风石之间的新交叉点 形成和滑膜炎。积极的影响包括为“普通痛风”建立一个新的疾病模式， 潜在的新的生物标志物，以及来自新型O-糖蛋白剂的可能的痛风治疗剂。

Abstract Gout is a highly prevalent disease manifesting most commonly as acute, episodic synovitis that characteristically is excruciatingly painful. Gout continues to grow as a public health problem. The disorder is promoted by elevated body stores of uric acid, and the clinical phenotypes of arthritis are caused by inflammatory responses associated with articular deposits of urate crystals. However, gout develops in only a minority subset of hyperuricemic subjects. Moreover, clinical responses to deposited urate crystals are highly variable, including the frequency and extent of acute arthritis, and progression to palpable subcutaneous tophi, chronic arthritis, and erosive joint damage. There is unmet need to define new therapy targets and biomarkers for incident gout and progression to erosive joint disease. The rationale for this high risk/high reward application is that by clarifying major gaps in knowledge in these areas, the work will be paradigm-shifting, and potentially identify new targets to help prevent and limit gout-associated morbidity. Emerging findings, including from certain arthropathies other than gout, suggest that altered extracellular matrix O-linked glycoprotein components such as the mucin-type boundary lubricant lubricin, and active urate pumping into the joint by an unidentified transport mechanism play a role in development of gout. Our scientific premise is that, in synovial fibroblast lining cells (FLS), mechanistically linked alterations in lubricin and other mucin-type extracellular matrix O-glycoproteins and increased urate secretion are in a mechanistic lop that promotes “common gout”, and progression to chronic, destructive synovitis. We will use primarily a combined candidate gene and reverse genetics approach to analyze a highly unusual observation, specifically a case of gout as an “experiment of nature”. The proband, an otherwise healthy female without hyperuricemia, at age 22 had onset of destructive hip synovitis, and asymmetric acute gouty arthritis flares of small and intermediate joints with classic toe joint gout erosions, and gout definitively confirmed. Collective preliminary data for proband whole genomic DNA, and serum glycomics, proteomics, and glycoproteomics suggest dysregulation in biosynthesis of lubricin and other mucin-type O-glycoproteins that normally serve as constitutive inhibitors of inflammation. Gene candidates are highly enriched in the “reactome” of TMEM171, an incompletely characterized transmembrane molecule implicated in urate transport and recently defined as a gout susceptibility gene. Specifically, the TMEM171 reactome comprises over 20 molecules involved in glycoprotein biosynthesis, more than 10 mucintype. O-glycoproteins, and over 20 ADAMTS protease superfamily members. The work aims to illuminate novel intersections between synovial extracellular matrix biology, urate metabolism and transport, tophus formation, and synovitis. Positive impact includes building a new disease paradigm for “common gout”, potential new biomarkers, and possible gout therapeutics from the novel class of O-glycoprotein agents.