{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T07:16:01Z","timestamp":1763968561975,"version":"3.41.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and cartilage\/bone damage. Intercellular messengers such as IL-1 and TNF play a crucial role in the pathophysiology of RA but have limited diagnostic and prognostic values. Therefore, we assessed whether the protein content of the recently discovered extracellular vesicles (EVs), which have gained attention in the pathogenesis of RA, correlates with disease activity parameters in RA patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified and quantified proteins in plasma-derived EVs (pEVs), isolated by size exclusion chromatography from 17 RA patients by mass spectrophotometry (MS). Quantified protein levels were correlated with laboratory and clinical parameters and the patient\u2019s own global assessment of their disease activity (PGA-VAS). In a second MS run, the pEV proteins of nine other RA patients were quantified and compared to those from nine healthy controls (HC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>No differences were observed in the concentration, size, and protein content of pEVs from RA patients. Proteomics revealed &amp;gt;95% overlapping proteins in RA-pEVs, compared to HC-pEVs (data are available via ProteomeXchange with identifier PXD046058). Remarkably, in both runs, the level of far more RA-pEV proteins correlated positively to PGA-VAS than to either clinical or laboratory parameters. Interestingly, all observed PGA-VAS positively correlated RA-pEV proteins were associated with the actin-cytoskeleton linker proteins, ezrin, and moesin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our observation suggests that PGA-VAS (loss of vitality) may have a different underlying pathological mechanism in RA, possibly related to enhanced muscle actin-cytoskeleton activity. Furthermore, our study contributes to the growing awareness and evidence that pEVs contain valuable biomarkers for diseases, with added value for RA patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2023.1247778","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T04:29:42Z","timestamp":1704947382000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Profiling of plasma extracellular vesicles identifies proteins that strongly associate with patient\u2019s global assessment of disease activity in rheumatoid arthritis"],"prefix":"10.3389","volume":"10","author":[{"given":"Onno J.","family":"Arntz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogier M.","family":"Thurlings","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esmeralda N.","family":"Blaney Davidson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal W. T. C.","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiel","family":"Vermeulen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marije I.","family":"Koenders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter M.","family":"van der Kraan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fons A. J.","family":"van de Loo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.autrev.2004.09.002","article-title":"Epidemiology of adult rheumatoid arthritis","volume":"4","author":"Alamanos","year":"2005","journal-title":"Autoimmun Rev"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.immuni.2017.02.006","article-title":"Immunopathogenesis of rheumatoid arthritis","volume":"46","author":"Firestein","year":"2017","journal-title":"Immunity"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","article-title":"2010 rheumatoid arthritis classification criteria: an American College of Rheumatology\/European league against rheumatism collaborative initiative","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheum"},{"key":"ref4","first-page":"13","article-title":"The natural history of rheumatoid arthritis","volume":"44","author":"Wolfe","year":"1996","journal-title":"J Rheumatol Suppl"},{"key":"ref5","first-page":"98","article-title":"Experimental development of the graphic rating method","volume":"18","author":"Hayes","year":"1921","journal-title":"Psychol Bull"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s40744-017-0063-5","article-title":"The patient global assessment of disease activity in rheumatoid arthritis: identification of underlying latent factors","volume":"4","author":"Challa","year":"2017","journal-title":"Rheumatol Therap"},{"key":"ref7","first-page":"286","article-title":"Extra-articular manifestations in rheumatoid arthritis","volume":"5","author":"Cojocaru","year":"2010","journal-title":"Maedica"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1097\/BOR.0000000000000697","article-title":"Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities?","volume":"32","author":"Andonian","year":"2020","journal-title":"Curr Opin Rheumatol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"CMAMD.S11481","DOI":"10.4137\/CMAMD.S11481","article-title":"Comorbidity profile among patients with rheumatoid arthritis and the impact on prescriptions trend","volume":"6","author":"Al-Bishri","year":"2013","journal-title":"Clin Med Insights Arthritis Musculoskeletal Disord"},{"year":"2005","author":"Fischer","key":"ref10"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s41927-017-0001-8","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets","volume":"1","author":"Alunno","year":"2017","journal-title":"BMC Rheumatol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1007\/s00018-011-0689-3","article-title":"Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles","volume":"68","author":"Gy\u00f6rgy","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.bbrc.2010.07.083","article-title":"Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein","volume":"399","author":"Tamai","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"5338","DOI":"10.3390\/ijms14035338","article-title":"Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications","volume":"14","author":"Corrado","year":"2013","journal-title":"Int J Mol Sci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41556-018-0250-9","article-title":"Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication","volume":"21","author":"Mathieu","year":"2019","journal-title":"Nat Cell Biol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"522","DOI":"10.3390\/biom11040522","article-title":"Alarming cargo: the role of exosomes in trauma-induced inflammation","volume":"11","author":"Walsh","year":"2021","journal-title":"Biomol Ther"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/s41598-020-57497-7","article-title":"A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum","volume":"10","author":"Brennan","year":"2020","journal-title":"Sci Rep"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e0236508","DOI":"10.1371\/journal.pone.0236508","article-title":"An optimized method for plasma extracellular vesicles isolation to exclude the copresence of biological drugs and plasma proteins which impairs their biological characterization","volume":"15","author":"Arntz","year":"2020","journal-title":"PLoS One"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/978-1-4939-7652-2_7","article-title":"Cushioned\u2013density gradient ultracentrifugation (C-DGUC): A refined and high performance method for the isolation, characterization, and use of exosomes","volume":"1740","author":"Li","year":"2018","journal-title":"Methods Mol Biol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wi\u015bniewski","year":"2009","journal-title":"Nat Methods"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/nbt.1511","article-title":"MaxQuant enables high peptide identification rates, individualized ppb-range mass accuracies and proteome-wide protein quantification","volume":"26","author":"Cox","year":"2008","journal-title":"Nat Biotechnol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","article-title":"The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences","volume":"50","author":"Perez-Riverol","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1007\/s00018-018-2773-4","article-title":"Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins","volume":"75","author":"Karimi","year":"2018","journal-title":"Cell Mol Life Sci"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"26913","DOI":"10.3402\/jev.v3.26913","article-title":"Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the international society for extracellular vesicles","volume":"3","author":"L\u00f6tvall","year":"2014","journal-title":"J Extracell Vesicles"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e1185","DOI":"10.1002\/cti2.1185","article-title":"Proteomic analysis of extracellular vesicles reveals an immunogenic cargo in rheumatoid arthritis synovial fluid","volume":"9","author":"Foers","year":"2020","journal-title":"Clin Transl Immunol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1615\/CritRevImmunol.2015012327","article-title":"The ezrin-radixin-moesin family of proteins in the regulation of B-cell immune response","volume":"35","author":"Pore","year":"2015","journal-title":"Crit Rev Immunol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s41927-018-0041-8","article-title":"A proteomic analysis of serum-derived exosomes in rheumatoid arthritis","volume":"2","author":"Tsuno","year":"2018","journal-title":"BMC Rheumatol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2021\/9421720","article-title":"Systemic proteomic analysis reveals distinct exosomal protein profiles in rheumatoid arthritis","volume":"2021","author":"Qin","year":"2021","journal-title":"J Immunol Res"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/proteomes7020018","article-title":"Proteome profiling of exosomes purified from a small amount of human serum: the problem of co-purified serum components","volume":"7","author":"Smolarz","year":"2019","journal-title":"Proteome"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1007\/s10495-009-0317-y","article-title":"Cell death in rheumatoid arthritis","volume":"14","author":"Korb","year":"2009","journal-title":"Apoptosis"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-021-02510-1","article-title":"Identification of neutrophil \u03b22-integrin LFA-1 as a potential mechanistic biomarker in ANCA-associated vasculitis via microarray and validation analyses","volume":"23","author":"Matsumoto","year":"2021","journal-title":"Arthritis Res Ther"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"4798","DOI":"10.1182\/blood-2011-11-392563","article-title":"NHERF-2 maintains endothelial homeostasis","volume":"119","author":"Bhattacharya","year":"2012","journal-title":"Blood"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"7747","DOI":"10.3390\/ijms21207747","article-title":"Sodium hydrogen exchanger regulatory factor-1 (NHERF1) regulates fetal membrane inflammation","volume":"21","author":"Kammala","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e0230317","DOI":"10.1371\/journal.pone.0230317","article-title":"Discordance between the patient\u2019s and physician\u2019s global assessment in rheumatoid arthritis: data from the REAL study\u2014Brazil","volume":"15","author":"Guimar\u00e3es","year":"2020","journal-title":"PLoS One"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-016-1151-6","article-title":"Patient global assessment in measuring disease activity in rheumatoid arthritis: a review of the literature","volume":"18","author":"Nikiphorou","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/acr.20685","article-title":"Determinants of discordance in patients' and physicians' rating of rheumatoid arthritis disease activity","volume":"64","author":"Khan","year":"2012","journal-title":"Arthritis Care Res"},{"key":"ref38","first-page":"17","article-title":"Clinical measures in rheumatoid arthritis: which are most useful in assessing patients?","volume":"21","author":"Ward","year":"1994","journal-title":"J Rheumatol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2574","DOI":"10.1002\/jcb.23183","article-title":"EBP50 is involved in the regulation of vascular smooth muscle cell migration and cytokinesis","volume":"112","author":"Baeyens","year":"2011","journal-title":"J Cell Biochem"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"36426","DOI":"10.1074\/jbc.M113.483339","article-title":"Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) and nuclear factor-\u03baB (NF-\u03baB): a feed-forward loop for systemic and vascular inflammation","volume":"288","author":"Leslie","year":"2013","journal-title":"J Biol Chem"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2867","DOI":"10.1161\/ATVBAHA.112.301172","article-title":"Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy","volume":"33","author":"Palladino","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/j.ajpath.2016.11.013","article-title":"Elevated expression of moesin in muscular dystrophies","volume":"187","author":"Pines","year":"2017","journal-title":"Am J Pathol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1523\/JNEUROSCI.3229-12.2013","article-title":"Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2\/3 receptors on nociceptors","volume":"33","author":"Joseph","year":"2013","journal-title":"J Neurosci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"210166","DOI":"10.1098\/rsob.210166","article-title":"Spatial activation of ezrin by epidermal growth factor receptor and focal adhesion kinase co-ordinates epithelial cell migration","volume":"11","author":"Chan","year":"2021","journal-title":"Open Biol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"L240","DOI":"10.1152\/ajplung.00355.2012","article-title":"Ezrin\/radixin\/moesin proteins differentially regulate endothelial hyperpermeability after thrombin","volume":"305","author":"Adyshev","year":"2013","journal-title":"Am J Phys Lung Cell Mol Phys"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e0153924","DOI":"10.1371\/journal.pone.0153924","article-title":"Possible biomarkers of chronic stress induced exhaustion-a longitudinal study","volume":"11","author":"Wallensten","year":"2016","journal-title":"PLoS One"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e04885","DOI":"10.7554\/eLife.04885","article-title":"Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs","volume":"4","author":"Madden","year":"2015","journal-title":"elife"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1247778\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T04:29:47Z","timestamp":1704947387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1247778\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,11]]},"references-count":47,"alternative-id":["10.3389\/fmed.2023.1247778"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2023.1247778","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2024,1,11]]},"article-number":"1247778"}}