Novel Synovial Role in Pathogenesis of Gout

滑膜在痛风发病机制中的新作用

• 批准号: 9810080
• 负责人: Robert A. Terkeltaub
• 金额: $ 18.62万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810080
• 关键词: ABCG2 gene; ADAMTS; Acute; Age; Amino Acid Sequence Databases; Anabolism; Area; Arthritis; Automobile Driving; Biological; Biological Markers; Biology; Candidate Disease Gene; Cells; Characteristics; Chronic; Clinical; Crystal Formation; Crystallization; Custom; DNA Sequence; Data; Defect; Deposition; Development; Disease; Drops; Enzymes; Extracellular Matrix; Female; Fibroblasts; Flare; Frequencies; Generations; Genetic study; Genomic DNA; Genomic Data Commons; Genomics; Glycoproteins; Gout; Gouty Arthritis; Hip region structure; Hyperuricemia; Image; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Interleukin-1; Interphalangeal joint of toe; Joints; Knock-out; Knowledge; Lead; Light; Lighting; Link; Lubricants; Mediator of activation protein; Metabolic Diseases; Metabolism; Minority; Molecular Chaperones; Morbidity - disease rate; Mucin 1 protein; Mucins; Mutation; Nature; O-Glycans Biosynthesis Pathway; Outcome; Pain; Palpable; Parents; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Polysaccharides; Process; Proteomics; Public Health; Pump; Quantitative Trait Loci; Risk; Role; Sampling; Serum; Small Interfering RNA; Specimen; Susceptibility Gene; Synovial Membrane; Synovitis; Testing; Therapeutic; Tissues; Toes; Transfection; Urate; Uric Acid; Variant; Work; arthropathies; cell behavior; clinical phenotype; enzyme pathway; experimental study; genetic approach; genome wide association study; glycoprotein biosynthesis; glycoproteomics; glycosylation; high reward; high risk; inhibitor/antagonist; joint injury; knock-down; lubricin; member; new therapeutic target; novel; novel marker; novel strategies; prevent; proband; purine metabolism; response; reverse genetics; sialylation; subcutaneous; targeted biomarker; urate transporter

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.

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 通常是极其痛苦的。痛风作为一个公共卫生问题继续增长。这种混乱是 由体内尿酸储存量增加促进，关节炎的临床表型是由 与尿酸盐晶体关节沉积相关的炎症反应。然而，痛风只在 高尿酸血症受试者的少数亚群。此外，临床上对沉积的尿酸盐晶体的反应很高。 可变的，包括急性关节炎的频率和程度，以及进展到可触及的皮下痛点， 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记物的需求尚未得到满足 用于痛风和侵蚀性关节疾病的进展。这种高风险/高回报的理由 应用是，通过澄清这些领域中的主要知识差距，这项工作将是范式转变，以及 有可能确定新的靶点，以帮助预防和限制痛风相关的发病率。新的发现，包括 来自痛风以外的某些关节疾病，表明改变了细胞外基质O-连接的糖蛋白 如粘液型边界润滑剂润滑剂和活性尿酸盐泵入关节 不明转运机制在痛风的发生发展中起一定作用。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类型细胞外的机械性改变 基质O-糖蛋白和尿酸分泌增加处于促进“普通痛风”的机械性障碍中， 并进展为慢性破坏性滑膜炎。我们将主要使用组合候选基因和反向 用遗传学的方法来分析一种非常不寻常的观察，特别是痛风的病例，将其视为一种 自然“。先证者是一名健康的女性，没有高尿酸血症，22岁时出现破坏性 髋关节滑膜炎和不对称性急性痛风性关节炎小关节和中等关节典型的脚趾关节 痛风侵蚀，和痛风明确确认。收集先证者和整个基因组DNA的初步数据， 血清糖组学、蛋白质组学和糖蛋白组学表明，润滑素和 其他粘蛋白类型的O-糖蛋白，通常用作炎症的结构性抑制物。基因 候选者高度富含TMEM171的反应体，TMEM171是一种未完全表征的跨膜 与尿酸转运有关的分子，最近被定义为痛风易感基因。具体地说， TMEM171反应体由20多个参与糖蛋白生物合成的分子组成，10多个 粘液型。O-糖蛋白和20多个ADAMTS蛋白酶超家族成员。这部作品旨在阐明 滑膜细胞外基质生物学、尿酸盐代谢和转运之间的新交叉 队形和滑膜炎。积极影响包括为“普通痛风”建立一种新的疾病模式， 潜在的新生物标志物，以及来自新型O-糖蛋白制剂的可能的痛风治疗药物。