{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:35:44Z","timestamp":1779291344032,"version":"3.51.4"},"reference-count":56,"publisher":"American Physiological Society","issue":"3","funder":[{"name":"NIAMS\/NIH","award":["R01AR067748"],"award-info":[{"award-number":["R01AR067748"]}]},{"name":"NIAMS\/NIH","award":["R01AR067748"],"award-info":[{"award-number":["R01AR067748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2018,9,1]]},"abstract":"<jats:p> Osteoarthritis (OA) is characterized by synovitis and synovial fibrosis. Synoviocytes are fibroblast-like resident cells of the synovium that are activated by transforming growth factor (TGF)-\u03b2 to proliferate, migrate, and produce extracellular matrix. Synoviocytes secrete hyaluronan (HA) and proteoglycan-4 (PRG4). HA reduces synovial fibrosis in vivo, and the Prg4<jats:sup>\u2212\/\u2212<\/jats:sup> mouse exhibits synovial hyperplasia. We investigated the antifibrotic effects of increased intracellular cAMP in TGF-\u03b2-stimulated human OA synoviocytes. TGF-\u03b21 stimulated collagen I (COL1A1), \u03b1-smooth muscle actin (\u03b1-SMA), tissue inhibitor of metalloproteinase (TIMP)-1, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) expression, and procollagen I, \u03b1-SMA, HA, and PRG4 production, migration, and proliferation of OA synoviocytes were measured. Treatment of OA synoviocytes with forskolin (10 \u03bcM) increased intracellular cAMP levels and reduced TGF-\u03b21-stimulated COL1A1, \u03b1-SMA, and TIMP-1 expression, with no change in PLOD2 expression. Forskolin also reduced TGF-\u03b21-stimulated procollagen I and \u03b1-SMA content as well as synoviocyte migration and proliferation. Forskolin (10 \u03bcM) increased HA secretion and PRG4 expression and production. A cell-permeant cAMP analog reduced COL1A1 and \u03b1-SMA expression and enhanced HA and PRG4 secretion by OA synoviocytes. HA and PRG4 reduced \u03b1-SMA expression and content, and PRG4 reduced COL1A1 expression and procollagen I content in OA synoviocytes. Prg4<jats:sup>\u2212\/\u2212<\/jats:sup> synovium exhibited increased \u03b1-SMA, COL1A1, and TIMP-1 expression compared with Prg4<jats:sup>+\/+<\/jats:sup> synovium. Prg4<jats:sup>\u2212\/\u2212<\/jats:sup> synoviocytes demonstrated strong \u03b1-SMA and collagen type I staining, whereas these were undetected in Prg4<jats:sup>+\/+<\/jats:sup> synoviocytes and were reduced with PRG4 treatment. We conclude that increasing intracellular cAMP levels in synoviocytes mitigates synovial fibrosis through enhanced production of HA and PRG4, possibly representing a novel approach for treatment of OA synovial fibrosis. <\/jats:p>","DOI":"10.1152\/ajpcell.00041.2018","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T21:28:23Z","timestamp":1528925303000},"page":"C432-C443","source":"Crossref","is-referenced-by-count":36,"title":["cAMP attenuates TGF-\u03b2\u2019s profibrotic responses in osteoarthritic synoviocytes: involvement of hyaluronan and PRG4"],"prefix":"10.1152","volume":"315","author":[{"given":"Marwa M.","family":"Qadri","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory D.","family":"Jay","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Rhode Island Hospital, Providence, Rhode Island"},{"name":"Department of Biomedical Engineering, Brown University, Providence, Rhode Island"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rennolds S.","family":"Ostrom","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Rhode Island Hospital, Providence, Rhode Island"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8925-4255","authenticated-orcid":false,"given":"Khaled A.","family":"Elsaid","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1301-5"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/art.39087"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/art.37996"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2004.025270"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2009.0210"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.9.5882"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/path.1635"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.1188"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.0104"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/ar3852"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.10.6696"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V1291853"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.067470"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1159\/000056791"},{"key":"B15","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/PL00020784","volume":"50","author":"Inoue H","year":"2001","journal-title":"Inflamm Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01847.x"},{"key":"B17","first-page":"594","volume":"27","author":"Jay GD","year":"2000","journal-title":"J Rheumatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/art.27550"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2014.08.008"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125192"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.090324"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.028951"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/art.21373"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-015-0842-5"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.72"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1229-9"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/ard.56.7.426"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1177\/036354659702500106"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/ar3010"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1101\/gad.231969.113"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/ar3286"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1042\/bj3540017"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-013-1740-5"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/art.38266"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2012.10.002"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200522263"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200701040"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25650"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23498"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.02.012"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2009.03.016"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.6.3363"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22037"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.159"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/boneres.2014.2"},{"key":"B47","first-page":"365","volume":"24","author":"Smith MD","year":"1997","journal-title":"J Rheumatol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.2174\/1874312901105010100"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/ar2073"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408704102"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-013-1143-4"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.219"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18061252"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R700036200"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X10378373"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801490105"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00041.2018","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T15:54:09Z","timestamp":1718639649000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00041.2018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,1]]},"references-count":56,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,9,1]]}},"alternative-id":["10.1152\/ajpcell.00041.2018"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00041.2018","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,1]]}}}