RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway

RA滑膜成纤维细胞外泌体（RA-EXo）通过AhR/TRAF2通路介导骨侵蚀

• 批准号: 10622327
• 负责人: HUANG-GE ZHANG
• 金额: --
• 依托单位: LOUISVILLE VA MEDICAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622327
• 关键词: ARA9 protein; Affect; Animal Model; Arthritis; Aryl Hydrocarbon Receptor; Attenuated; Autoimmune Diseases; Biological; Biological Markers; Biological Response Modifiers; Biotin; Biotinylation; Bone Development; CRISPR/Cas technology; Cartilage; Cells; Chondrocytes; Chronic; Complex; Cytosol; Data; Development; Diagnosis; Dissociation; Endothelial Cells; Exocytosis; Extracellular Space; Fibroblasts; Future; Guidelines; Health Status; Heat-Shock Proteins 90; High Prevalence; Human; Hyperplasia; Immune; Immunocompetent; Implant; Individual; Inflammation; Invaded; Knock-out; Knowledge; Label; Ligase; MAPK8 gene; Mediating; Mediator; Military Personnel; Modeling; Molecular Target; Mus; Mutate; NF-kappa B; Osteitis; Outcome; Outcome Study; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacotherapy; Phosphorylation; Phosphotransferases; Play; Population; Predictive Value; Prevention; Process; Proliferating; Proteins; Publishing; Receptor Activation; Research; Rheumatoid Arthritis; Role; SCID Mice; Severities; Site; Sorting; Synovial Cell; Synovial Fluid; Synovial Membrane; System; TNF Receptor-Associated Factors; TNF gene; TNF receptor-associated factor 2; Testing; Therapeutic; Tissues; United States Department of Veterans Affairs; Vesicle; Veterans; Virulence Factors; Woman; arthritis therapy; arthropathies; bone; bone erosion; cartilage degradation; cell type; disability; exosome; experimental study; extracellular; improved; in vivo; intercellular communication; joint destruction; joint inflammation; joint injury; member; men; mouse model; novel therapeutics; patient population; personalized medicine; precision drugs; predictive marker; prevent; protein protein interaction; receptor expression; recruit; valosin-containing protein

Rheumatoid Arthritis (RA) is more prevalent among veterans than nonveterans. Women comprise an increasing proportion of military personnel and have a higher prevalence of arthritis than men. Thus, RA is a highly relevant problem for the Veterans Administration (VA). In RA synovium, rheumatoid arthritis synovial fibroblasts (RASFs) are hyper proliferated, the leading cell type in the terminal layer of the hyperplastic synovial tissue that invades and degrades adjacent cartilage and bone. TRAF2 mediated activation of NF-B and JNK leads to hyperproliferation of RASFs, chronic inflammation and the erosive arthritis which is the hallmark of RA. How NF- B and JNK is activated in rheumatoid synovial fibroblast remains elusive, though studies have demonstrated that the blockade of TNF mediated activation of NF-B and JNK attenuates the RA progression. However, a large population of RA patients are non-response to anti-TNF therapy. Research from our group and others has shown that exosomes released from rheumatoid synovial fibroblasts (RA-Exo) contribute to RA pathogenicity and inflammation in several different animal models of joint disease, including RA. Exosomes are small cell derived vesicles that are 30-100 nm in size and of endocytic origin. Exosomes released by exocytosis into the extracellular space, where they are considered important drivers of intercellular communication. Exosomes in synovial fluid of RA patients can lead to inflammation, degeneration of cartilage, and destruction of joints. However, exosomes in synovial fluid could be released by different types of cells including RASFs in the synovium. Which cell types release exosomes that contribute to joint inflammation and degeneration of cartilage is not well studied. Of particular relevance to this proposal, we have demonstrated that RASF exosomes (RA-Exo) activate the TNF- receptor-associated factor 2 (TRAF2) mediated activation of the NF-B and JNK pathways is promoted by stabilization of TRAF2. More importantly, our preliminary data clearly demonstrate that aryl hydrocarbon receptor (AhR) expression is significantly elevated in synovium from patients with RA. Expression positively correlates with bone erosion and is localized with TRAF2, strongly supporting the relevance of this pathway in the pathogenesis of RA in humans. Mechanistically, AhR is enriched in the RA-Exo and RA-Exo AhR is required for stabilizing TRAF2. Our OVERALL HYPOTHESIS is that targeting AhR centered networks in RA-Exo leads to TRAF2 degradation, and the prevention of TRAF2 mediated activation of the NF-B and JNK pathways in RASFs. Therefore, disruption of the AhR network in RA exosomes will eliminate/attenuate bone erosion and inflammation by affecting RA-Exo mediated pathways contributing to the development of bone erosion in synovium of RA patients. Our plan to accomplish this objective are outlined in these three specific aims: 1. Identify the RA-Exo AhR network that results in the development of arthritis in the mouse models. 2. Determine whether RA-Exo AhR-associated kinase activity mediates dissociation of TRAF2AF from the TRAF2 complex. 3. Determine whether blocking the recruitment of VCIP135 to RA-Exo AhR results in preventing the development of erosive arthritis in the huRASF/SCID mouse model. The positive outcome of this study for future products would provide a basis for developing mechanism-driven novel drugs for RA therapy. Moreover, it is of high value for predicting biomarkers from RA-Exo of non-responsive individuals prior to commencing anti-TNF or personalized drug therapy.

类风湿关节炎（RA）在退伍军人中比非退伍军人更普遍。妇女组成了