{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T17:05:33Z","timestamp":1775581533898,"version":"3.50.1"},"reference-count":54,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,8,18]],"date-time":"2016-08-18T00:00:00Z","timestamp":1471478400000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Limited range of motion (ROM) as a result of joint contracture in treatment associated with joint immobilization or motor paralysis is a critical issue. However, its molecular mechanism has not been fully clarified and a therapeutic approach is not yet established.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the present study, we investigated its molecular mechanism, focusing on the role of a transcription factor, hypoxia inducible factor\u20101 (HIF\u20101), which regulates the expression of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), and evaluated the possibility of molecular therapy to inhibit HIF\u20101 activation by ribbon\u2010type decoy oligonucleotides (ODNs) for HIF\u20101 using immobilized knee animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a mouse model, ROM of the immobilized knee significantly decreased in a time\u2010dependent manner, accompanied by synovial hypertrophy. Immunohistochemical studies suggested that CTGF and VEGF are implicated in synovial hypertrophy with fibrosis. CTGF and VEGF were up\u2010regulated at both the mRNA and protein levels at 1 and 2 weeks after immobilization, subsequent to up\u2010regulation of HIF\u20101 mRNA and transcriptional activation of HIF\u20101. Of importance, intra\u2010articular transfection of decoy ODNs for HIF\u20101 in a rat model successfully inhibited transcriptional activation of HIF\u20101, followed by suppression of expression of CTGF and VEGF, resulting in attenuation of restricted ROM, whereas transfection of scrambled decoy ODNs did not.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present study demonstrates the important role of HIF\u20101 in the initial progression of immobilization\u2010induced joint contracture, and indicates the possibility of molecular treatment to prevent the progression of joint contracture prior to intervention with physical therapy. Copyright \u00a9 2016 John Wiley &amp; Sons, Ltd.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.2891","type":"journal-article","created":{"date-parts":[[2016,6,28]],"date-time":"2016-06-28T23:26:45Z","timestamp":1467156405000},"page":"180-192","source":"Crossref","is-referenced-by-count":19,"title":["Therapeutic effect of intra\u2010articular injection of ribbon\u2010type decoy oligonucleotides for hypoxia inducible factor\u20101 on joint contracture in an immobilized knee animal model"],"prefix":"10.1002","volume":"18","author":[{"given":"Daisuke","family":"Sotobayashi","sequence":"first","affiliation":[{"name":"Graduate School of Health Sciences Morinomiya University of Medical Sciences  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirohisa","family":"Kawahata","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences Morinomiya University of Medical Sciences  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natsuki","family":"Anada","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences Morinomiya University of Medical Sciences  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Ogihara","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences Morinomiya University of Medical Sciences  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Clinical Gene Therapy, Graduate School of Medicine Osaka University  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motokuni","family":"Aoki","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences Morinomiya University of Medical Sciences  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,8,18]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4160-4007-1.50119-X"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003086-198706000-00006"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00409.2014"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.L.01741"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.orthres.2003.08.012"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-9993(00)90213-2"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/03008200590954131"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2006.01613.x"},{"key":"e_1_2_6_10_1","first-page":"351","article-title":"Synovial adhesions are more important than pannus proliferation in the pathogenesis of knee joint contracture after immobilization: an experimental investigation in the rat","volume":"27","author":"Trudel G","year":"2000","journal-title":"J Rheumatol"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3109\/2000-1967-207"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-9993(03)00233-8"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/000164702320155365"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.3109\/2000-1967-223"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/BLO.0b013e3180312c01"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/03008200802412454"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3109\/03008207.2013.786056"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.82.10.1023"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.027029"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1980"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.1077"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.208"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652312803519814"},{"key":"e_1_2_6_24_1","first-page":"286","article-title":"An examination of the mechanism of ligament contracture","volume":"227","author":"Wilson CJ","year":"1988","journal-title":"Clin Orthop Relat Res"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2005.10.015"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.1100180208"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004180050434"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871522211313020006"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfn699"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfm715"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.5432\/ijshs.3.91"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00035.2007"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00331-09"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-4-440"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705687"},{"key":"e_1_2_6_36_1","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1096\/fj.02-0420fje","article-title":"Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells \u2013 role of hypoxia\u2010inducible transcription factors","volume":"16","author":"Rose F","year":"2002","journal-title":"FASEB J"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0910283"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.51.32529"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00245.2004"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2006.03199.x"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphs.2014.12.011"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00419.x"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780341206"},{"key":"e_1_2_6_44_1","first-page":"646","article-title":"Hypoxia appears at pre\u2010arthritic stage and shows co\u2010localization with early synovial inflammation in collagen induced arthritis","volume":"26","author":"Jeon CH","year":"2008","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.3.1230"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.16.9.4604"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1089\/ard.1991.1.141"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301875"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301724"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.38.1.48"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203239"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-002-0066-1"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0329fje"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/9467"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12255"}],"container-title":["The Journal of Gene Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjgm.2891","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jgm.2891","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T05:31:50Z","timestamp":1695706310000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jgm.2891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8]]},"references-count":54,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1002\/jgm.2891"],"URL":"https:\/\/doi.org\/10.1002\/jgm.2891","archive":["Portico"],"relation":{},"ISSN":["1099-498X","1521-2254"],"issn-type":[{"value":"1099-498X","type":"print"},{"value":"1521-2254","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8]]}}}