Role of PTPRS in Rheumatoid Arthritis

PTPRS 在类风湿关节炎中的作用

• 批准号: 10705192
• 负责人: Nunzio Bottini
• 金额: $ 45.73万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705192
• 关键词: Address; Aggressive behavior; Antirheumatic Agents; Arthritis; Binding; Biochemical; Biological Assay; Biology; Cell Line; Cells; Cellular biology; Clinic; Coculture Techniques; Cytoskeletal Proteins; Cytoskeleton; Data; Degenerative polyarthritis; Development; Dimerization; Disease; Disease remission; Drug Targeting; Electrons; Endothelial Cells; Endothelium; Enzymes; Epigenetic Process; Extracellular Domain; Fibroblasts; Funding; Genes; Genetic Transcription; Glycosaminoglycans; Goals; Grant; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Immune; Immunoglobulin Domain; Immunosuppressive Agents; In Vitro; Incubated; Inflammation; Invaded; Joints; Knowledge; Lead; Mediating; Membrane; Microscopy; Molecular; Morbidity - disease rate; Mus; Nature; Pathway interactions; Patients; Pattern; Permeability; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Protein Dephosphorylation; Protein Family; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proteoglycan; Publishing; Regulation; Reporting; Rheumatoid Arthritis; Role; Series; Side; Signal Transduction Inhibition; Surface; Swelling; Synovial Membrane; TNF gene; Therapeutic; Therapeutic Agents; Translating; Validation; Work; arthritis therapy; cell behavior; cell motility; design; disorder control; extracellular; ezrin; immunoregulation; imprint; in vivo; innovation; interest; joint destruction; joint inflammation; joint injury; migration; mouse model; neutrophil; novel; novel therapeutics; overexpression; polysulfated glycosaminoglycan; protein expression; recruit; structural biology; syndecan-4; therapeutic target

ABSTRACT Fibroblast-like synoviocytes (FLS) are joint-lining non-hematopoietic cells that in rheumatoid arthritis (RA) contribute to local joint inflammation and damage. There is interest in discovering FLS-directed therapeutic agents that could be combined with current immunosuppressant disease-modifying anti-rheumatic agents (DMARDs). This renewal proposal focuses on understanding the mechanism of action and regulation of the tyrosine phosphatase PTPRS, which plays a critical role in FLS migration and invasion. In the first cycle of this grant, we have shown that PTPRS is an important regulator of FLS aggressiveness during RA and developed an approach to modulate PTPRS function in rheumatoid FLS. Our studies showed that on the surface of RA FLS, PTPRS is kept in an inactive state through specific binding to the heparan sulfate (HS)- proteoglycan syndecan-4 through a mechanism called the proteoglycan switch. Treatment of RA FLS with a decoy fragment of PTPRS encompassing its two most extracellular proteoglycan-binding immunoglobulin domains (called Ig1&2) causes detachment of PTPRS from syndecan-4. This leads to PTPRS-dependent inhibition of migration and invasiveness via dephosphorylation of the PTPRS substrate ezrin. In vivo administration of Ig1&2 reverses arthritis in multiple mouse models via a non-immunological mechanism. We also find that PTPRS expression is inhibited on RA FLS by tumor necrosis factor alpha, suggesting that PTPRS expression is regulated by joint inflammation. In the second cycle of the grant, we would like to deepen our knowledge of the mechanism of action and regulation of PTPRS in FLS and RA. Here we propose to a series of mechanistic studies in primary human FLS and mouse models of RA aimed at understanding the regulation of PTPRS expression in RA FLS (Aims 1) and how Ig1&2 and PTPRS regulate FLS-induced inflammation in arthritis (Aim 2). We will also use biochemical, structural, and cellular biology approaches to understand the key molecular determinants for PTPRS regulation by syndecan-4 (Aim 3). Our long-term goal remains to understand the biology of PTPRS in RA FLS, which will help to complete the validation of the PTPRS-regulated pathway as a therapeutic target for RA.

抽象的 成纤维细胞样滑膜细胞 (FLS) 是类风湿性关节炎 (RA) 中的关节内膜非造血细胞 导致局部关节炎症和损伤。人们对发现 FLS 导向的治疗方法很感兴趣 可以与现有的免疫抑制剂缓解疾病抗风湿药物联合使用的药物 （DMARD）。该更新提案的重点是了解该药物的作用机制和监管 酪氨酸磷酸酶 PTPRS，在 FLS 迁移和侵袭中发挥关键作用。 在本次资助的第一个周期中，我们已经证明 PTPRS 是 FLS 攻击性的重要调节因子。 RA 并开发了一种调节类风湿 FLS 中 PTPRS 功能的方法。我们的研究表明，在 在 RA FLS 表面，PTPRS 通过与硫酸乙酰肝素 (HS) 特异性结合而保持非活性状态 - 蛋白多糖 syndecan-4 通过一种称为蛋白多糖开关的机制。 RA FLS 的治疗 PTPRS 的诱饵片段，包含其两个最胞外蛋白聚糖结合免疫球蛋白 域（称为 Ig1&2）导致 PTPRS 从 syndecan-4 分离。这导致 PTPRS 依赖 通过 PTPRS 底物埃兹蛋白 (ezrin) 去磷酸化抑制迁移和侵袭。体内 在多种小鼠模型中，施用 Ig1&2 可通过非免疫机制逆转关节炎。我们 还发现 RA FLS 上的 PTPRS 表达被肿瘤坏死因子 α 抑制，表明 PTPRS 表达受关节炎症调节。 在第二轮资助中，我们希望加深对作用机制和 FLS 和 RA 中 PTPRS 的调节。在这里，我们建议对原发性人类 FLS 进行一系列机制研究 和 RA 小鼠模型，旨在了解 RA FLS 中 PTPRS 表达的调节（目标 1）和 Ig1&2 和 PTPRS 如何调节 FLS 诱导的关节炎炎症（目标 2）。我们还将使用生化， 结构和细胞生物学方法来了解 PTPRS 调节的关键分子决定因素 通过 syndecan-4（目标 3）。 我们的长期目标仍然是了解 RA FLS 中 PTPRS 的生物学，这将有助于完成 验证 PTPRS 调节途径作为 RA 治疗靶点。

项目成果

Receptor Protein Tyrosine Phosphatase α-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice.

• DOI: 10.1002/art.39442
• 发表时间: 2016-02
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Stanford SM;Svensson MN;Sacchetti C;Pilo CA;Wu DJ;Kiosses WB;Hellvard A;Bergum B;Muench GR;Elly C;Liu YC;den Hertog J;Elson A;Sap J;Mydel P;Boyle DL;Corr M;Firestein GS;Bottini N
• 通讯作者: Bottini N

Targeting Tyrosine Phosphatases: Time to End the Stigma.

• DOI: 10.1016/j.tips.2017.03.004
• 发表时间: 2017-06
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Stanford SM;Bottini N
• 通讯作者: Bottini N

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain.

RPTPα 磷酸酶活性受膜远端催化域变构调节。

• DOI: 10.1074/jbc.ra119.011808
• 发表时间: 2020
• 期刊: The Journal of biological chemistry
• 作者: Wen,Yutao;Yang,Shen;Wakabayashi,Kuninobu;Svensson,MattiasND;Stanford,StephanieM;Santelli,Eugenio;Bottini,Nunzio
• 通讯作者: Bottini,Nunzio