{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:14:16Z","timestamp":1790316856337,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,8,6]],"date-time":"2018-08-06T00:00:00Z","timestamp":1533513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c; scleroderma) is a chronic disease that affects the skin and various internal organs. Dermal fibrosis is a major component of this disease. The mechanisms that promote dermal fibrosis remain elusive. Elevations in tissue adenosine levels and the subsequent engagement of the profibrotic A<jats:sub>2B<\/jats:sub> adenosine receptor (<jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B) have been shown to regulate fibrosis in multiple organs including the lung, kidney, and penis; however, the role of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B in dermal fibrosis has not been investigated. We undertook this study to test our hypothesis that elevated expression of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B in the skin drives the development of dermal fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed the involvement of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B in the regulation of dermal fibrosis using a well\u2010established mouse model of dermal fibrosis. Using an orally active <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B antagonist, we demonstrated how inhibition of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B results in reduced dermal fibrosis in 2 distinct experimental models. Finally, using human dermal fibroblasts, we characterized the expression of adenosine receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that levels of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B were significantly elevated in dermal fibrosis and that the therapeutic blockade of this receptor in vivo using an <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B antagonist could reduce the production of profibrotic mediators in the skin and attenuate dermal fibrosis. Antagonism of <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B resulted in reduced numbers of arginase\u2010expressing macrophages and myofibroblasts and in reduced levels of the extracellular matrix proteins fibronectin, collagen, and hyaluronan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings identify <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B as a potential profibrotic regulator in dermal fibrosis and suggest that <jats:styled-content style=\"fixed-case\">ADORA<\/jats:styled-content>2B antagonism may be a useful approach for the treatment of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40554","type":"journal-article","created":{"date-parts":[[2018,5,17]],"date-time":"2018-05-17T06:53:09Z","timestamp":1526539989000},"page":"1673-1684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Antifibrotic Effect of A<sub>2B<\/sub> Adenosine Receptor Antagonism in a Mouse Model of Dermal Fibrosis"],"prefix":"10.1002","volume":"70","author":[{"given":"Harry","family":"Karmouty\u2010Quintana","sequence":"first","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose G.","family":"Molina","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kemly","family":"Philip","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bellocchi","sequence":"additional","affiliation":[{"name":"McGovern Medical School, Houston, Texas Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"Gudenkauf","sequence":"additional","affiliation":[{"name":"McGovern Medical School, Houston, Texas Texas Tech University Health Sciences Center Lubbock"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Wu","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning\u2010Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Collum","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junsuk","family":"Ko","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep K.","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Weng","sequence":"additional","affiliation":[{"name":"McGovern Medical School Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)68737-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31139"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2741\/s22"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402132"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-89615-9_8"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-009-0251-4"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.04.003"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-0997-1"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2004-0103OC"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-260182"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27303"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-200907"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.300166"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-144147"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2012.32"},{"key":"e_1_2_8_17_1","first-page":"299","article-title":"Inhibition of fibrosis in TSK mice by blocking mast cell degranulation","volume":"14","author":"Walker MA","year":"1987","journal-title":"J Rheumatol"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2003-0118OC"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.01.008"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3073"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009224"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022667"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0089OC"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(02)00045-7"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00258.2005"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.3.1937"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070952"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.08.024"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-241646"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21974"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4229"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00232-4"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13947"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep109"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445-5994.2007.01370.x"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.065078"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-011-0824-5"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00350.2015"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.098293"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.40554","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40554","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T18:44:13Z","timestamp":1759949053000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.40554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,6]]},"references-count":38,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1002\/art.40554"],"URL":"https:\/\/doi.org\/10.1002\/art.40554","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,6]]},"assertion":[{"value":"2016-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}