{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:43:15Z","timestamp":1782452595448,"version":"3.54.5"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,3,24]],"date-time":"2017-03-24T00:00:00Z","timestamp":1490313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor \u03ba-light-chain-enhancer of activated B cells (NF-\u03baB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin (IL)-1\u03b2 and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.<\/jats:p>","DOI":"10.3390\/ijms18040697","type":"journal-article","created":{"date-parts":[[2017,3,24]],"date-time":"2017-03-24T11:38:27Z","timestamp":1490355507000},"page":"697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Role and Function of A2A and A3 Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis"],"prefix":"10.3390","volume":"18","author":[{"given":"Annalisa","family":"Ravani","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Vincenzi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bortoluzzi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant\u2019Anna, 44124 Cona, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Padovan","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant\u2019Anna, 44124 Cona, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-1428","authenticated-orcid":false,"given":"Silvia","family":"Pasquini","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Gessi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Merighi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier","family":"Borea","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0499-5773","authenticated-orcid":false,"given":"Marcello","family":"Govoni","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant\u2019Anna, 44124 Cona, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-1348","authenticated-orcid":false,"given":"Katia","family":"Varani","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.tips.2016.02.006","article-title":"Adenosine as a multi-signalling guardian angel in human diseases: When, where and how does it exert its protective effects?","volume":"37","author":"Borea","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1124\/pr.113.008540","article-title":"The A3 adenosine receptor: History and perspectives","volume":"67","author":"Borea","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1517\/13543784.2011.627853","article-title":"Adenosine receptor targeting in health and disease","volume":"20","author":"Gessi","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/med.21344","article-title":"History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents","volume":"35","author":"Preti","year":"2015","journal-title":"Med. Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.bbamem.2010.09.020","article-title":"Adenosine receptors and cancer","volume":"1808","author":"Gessi","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrd2638","article-title":"Adenosine receptors: Therapeutic aspects for inflammatory and immune diseases","volume":"7","author":"Linden","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.ejphar.2011.06.049","article-title":"CGS 21680, an agonist of the adenosine A2A receptor, decreases acute lung inflammation","volume":"668","author":"Impellizzeri","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1164\/rccm.200506-869OC","article-title":"Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease","volume":"173","author":"Varani","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1096\/fj.09-141044","article-title":"A2A adenosine receptor overexpression and functionality, as well as TNF-\u03b1 levels, correlate with motor symptoms in Parkinson\u2019s disease","volume":"24","author":"Varani","year":"2010","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1002\/eji.201343314","article-title":"Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated","volume":"43","author":"Vincenzi","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.autrev.2010.07.019","article-title":"The role of adenosine receptors in rheumatoid arthritis","volume":"10","author":"Varani","year":"2010","journal-title":"Autoimmun. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S204","DOI":"10.1016\/j.jaci.2009.10.067","article-title":"Immunologic rheumatic disorders","volume":"125","author":"Joseph","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_13","first-page":"6097417","article-title":"Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: A systematic review","volume":"2016","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1002\/art.24794","article-title":"Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor \u03b1 but not methotrexate","volume":"60","author":"Varani","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R197","DOI":"10.1186\/ar3527","article-title":"A2A and A3 adenosine receptor expression in rheumatoid arthritis: Upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release","volume":"13","author":"Varani","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vincenzi, F., Padovan, M., Targa, M., Corciulo, C., Giacuzzo, S., Merighi, S., Gessi, S., Govoni, M., Borea, P.A., and Varani, K. (2013). A2A adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054195"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.3899\/jrheum.110111","article-title":"CGS 21680, an agonist of the adenosine A2A receptor, reduces progression of murine type II collagen-induced arthritis","volume":"38","author":"Mazzon","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"236","DOI":"10.4329\/wjr.v7.i9.236","article-title":"Ankylosing spondylitis: A state of the art factual backbone","volume":"7","author":"Attaya","year":"2015","journal-title":"World J. Radiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e3060","DOI":"10.1097\/MD.0000000000003060","article-title":"Comparative effectiveness of biologic therapy regimens for ankylosing spondylitis: A systematic review and a network meta-analysis","volume":"95","author":"Chen","year":"2016","journal-title":"Medicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.intimp.2014.05.031","article-title":"Evaluation of circulating levels of inflammatory and bone formation markers in axial spondyloarthritis","volume":"21","author":"Vicente","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1177\/1759720X15595966","article-title":"Making the next steps in psoriatic arthritis management: Current status and future directions","volume":"7","author":"Sritheran","year":"2015","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1007\/s10067-016-3202-4","article-title":"The A3 adenosine receptor (A3AR): Therapeutic target and predictive biological marker in rheumatoid arthritis","volume":"35","author":"Fishman","year":"2016","journal-title":"Clin. Rheumatol."},{"key":"ref_23","first-page":"S21","article-title":"How does methotrexate suppress inflammation?","volume":"28","author":"Cronstein","year":"2010","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1590\/abd1806-4841.20153689","article-title":"Adenosine: An endogenous mediator in the pathogenesis of psoriasis","volume":"90","author":"Festugato","year":"2015","journal-title":"An. Bras. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"555","DOI":"10.4049\/jimmunol.175.1.555","article-title":"Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses","volume":"175","author":"Ralph","year":"2005","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.bcp.2012.01.001","article-title":"Apremilast mechanism of action and application to psoriasis and psoriatic arthritis","volume":"83","author":"Schafer","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1136\/ard.2009.108233","article-title":"The development of Assessment of Apondyloarthritis international Society classification criteria for axial spondyloarthritis (part II): Validation and final selection","volume":"68","author":"Rudwaleit","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1002\/art.21972","article-title":"CASPAR Study Group, Classification criteria for psoriatic arthritis: Development of new criteria from a large international study","volume":"54","author":"Taylor","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.berh.2016.02.002","article-title":"New immune cells in spondyloarthritis: Key players or innocent bystanders?","volume":"29","author":"Venken","year":"2015","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cellimm.2009.03.020","article-title":"The anti-inflammatory target A3 adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn\u2019s disease","volume":"258","author":"Ochaion","year":"2009","journal-title":"Cell Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.drudis.2011.10.007","article-title":"Pharmacological and therapeutic effects of A3 adenosine receptor agonists","volume":"17","author":"Fishman","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_32","first-page":"227","article-title":"Signaling via the NF\u03baB system, Wiley Interdiscip","volume":"8","author":"Mitchell","year":"2016","journal-title":"Rev. Syst. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13075-015-0527-3","article-title":"Non-canonical NF-\u03baB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?","volume":"17","author":"Noort","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.5604\/17322693.1184460","article-title":"Activity of JAK\/STAT and NF-\u03baB in patients with axial spondyloarthritis","volume":"69","author":"Sokolik","year":"2015","journal-title":"Postep. Hig. Med. Doswiadczalnej."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1111\/bph.12227","article-title":"Activation of adenosine A2A receptor reduces osteoclast formation via PKA- and ERK1\/2-mediated suppression of NF\u03baB nuclear translocation","volume":"169","author":"Mediero","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.bcp.2008.05.032","article-title":"The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB\/Akt and NF-\u03baB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats","volume":"76","author":"Ochaion","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrrheum.2016.178","article-title":"Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases","volume":"13","author":"Cronstein","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1097\/BOR.0000000000000069","article-title":"The interleukin-23\/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis","volume":"26","author":"Yeremenko","year":"2014","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.semarthrit.2015.10.001","article-title":"Italian board for the TAilored BIOlogic therapy (ITABIO), Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis","volume":"45","author":"Cantini","year":"2016","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17068","DOI":"10.4238\/2015.December.16.7","article-title":"Serum matrix metalloproteinases-3 levels in patients with ankylosing spondylitis","volume":"14","author":"Gao","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1177\/1535370213506435","article-title":"Serological markers in psoriatic arthritis: Promising tools","volume":"238","author":"Ramonda","year":"2013","journal-title":"Exp. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1186\/s13075-014-0429-9","article-title":"Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis","volume":"16","author":"Dancevic","year":"2014","journal-title":"Arthritis Res. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/697\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:31:11Z","timestamp":1760207471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,24]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4]]}},"alternative-id":["ijms18040697"],"URL":"https:\/\/doi.org\/10.3390\/ijms18040697","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,24]]}}}