{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:29:10Z","timestamp":1790137750581,"version":"4.0.1"},"reference-count":52,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2019,11]]},"abstract":"Objective<\/jats:title>To assess the preclinical efficacy and mechanism of action of an anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 monoclonal antibody (mA<\/jats:styled-content>b) in systemic sclerosis (SS<\/jats:styled-content>c).<\/jats:p><\/jats:sec>Methods<\/jats:title>Cultured human dermal fibroblasts were used to evaluate the direct effect of anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b on fibroblasts. In addition, bleomycin\u2010induced and growth factor\u2013induced models of SS<\/jats:styled-content>c were used to investigate the effect of anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b on leukocyte infiltration, collagen deposition, and vascular damage in the skin.<\/jats:p><\/jats:sec>Results<\/jats:title>Anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b treatment significantly inhibited Smad3 phosphorylation (P<\/jats:italic> < 0.05) and expression of type I collagen and fibronectin 1 (P<\/jats:italic> < 0.01) in dermal fibroblasts stimulated with transforming growth factor \u03b21 (TGF<\/jats:styled-content>\u03b21). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 levels (P<\/jats:italic> < 0.05) and augmented lesional CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 expression. Simultaneous administration of anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b or CX<\/jats:styled-content>3<\/jats:sub>CR<\/jats:styled-content>1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin (P<\/jats:italic> < 0.05). Injection of bleomycin induced expression of pS<\/jats:styled-content>mad3 and TGF<\/jats:styled-content>\u03b21 in the skin, which was inhibited by anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b. Further, the dermal infiltration of CX<\/jats:styled-content>3<\/jats:sub>CR<\/jats:styled-content>1+ cells, macrophages (inflammatory and alternatively activated [M2\u2010like] subsets), and CD<\/jats:styled-content>3+ cells significantly decreased following anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b therapy (P<\/jats:italic> < 0.05), as did the enhanced skin expression of fibrogenic molecules, such as thymic stromal lymphopoietin and secreted phosphoprotein 1 (P<\/jats:italic> < 0.05). However, the treatment did not significantly reduce established skin fibrosis. In the second model, simultaneous anti\u2010mCX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGF<\/jats:styled-content>\u03b2 and connective tissue growth factor (P<\/jats:italic> < 0.01).<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Anti\u2010CX<\/jats:styled-content>3<\/jats:sub>CL<\/jats:styled-content>1 mA<\/jats:styled-content>b therapy may be a novel approach for treating early skin fibrosis in inflammation\u2010driven fibrotic skin disorders such as SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41009","type":"journal-article","created":{"date-parts":[[2019,6,7]],"date-time":"2019-06-07T07:23:54Z","timestamp":1559892234000},"page":"1923-1934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX<\/scp>3<\/sub>CL<\/scp>1\/CX<\/scp>3<\/sub>CR<\/scp>1 Pathway in Experimental Mouse Models of Systemic Sclerosis"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3548-8416","authenticated-orcid":false,"given":"Vu H.","family":"Luong","sequence":"first","affiliation":[{"name":"University of Fukui, Fukui, Japan, and Hanoi Medical University Hanoi Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1164-6088","authenticated-orcid":false,"given":"Akira","family":"Utsunomiya","sequence":"additional","affiliation":[{"name":"University of Fukui Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-3383","authenticated-orcid":false,"given":"Takenao","family":"Chino","sequence":"additional","affiliation":[{"name":"University of Fukui Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le H.","family":"Doanh","sequence":"additional","affiliation":[{"name":"Hanoi Medical University Hanoi Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1617-086X","authenticated-orcid":false,"given":"Takashi","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Kanazawa University Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Obara","sequence":"additional","affiliation":[{"name":"Eisai Company, Ltd. Tsukuba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Kuboi","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ishii","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Machinaga","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Ogasawara","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Ikeda","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsu","family":"Kawano","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Imai","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4934-5205","authenticated-orcid":false,"given":"Noritaka","family":"Oyama","sequence":"additional","affiliation":[{"name":"University of Fukui Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3738-2682","authenticated-orcid":false,"given":"Minoru","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"University of Fukui Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.2"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3066"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210823"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00174-2"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.7.4410"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2448"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1255354"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210189"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2009.26"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/385640a0"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-348946"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80438-9"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.8.1413"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022156"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1271-7"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2003.018705"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.1.569"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2012.10.010"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.11.7010"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6987"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40688"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxz006"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40688"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00528.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1534-y"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37933"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/pin.12627"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40169-015-0047-4"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37859"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202279"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2015.11.008"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.160408"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5454.860"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399411001839"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr221"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP085104"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130312"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e3283324f80"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201010-1719OC"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403209"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kel295"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.06.001"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210229"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2012.32"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0206545"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1024"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/cti.2013.2"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213031"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0923-1811(01)00128-1"},{"key":"e_1_2_9_52_1","first-page":"275","article-title":"Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis","volume":"33","author":"Matsushita T","year":"2006","journal-title":"J Rheumatol"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2017.1337056"}],"container-title":["Arthritis & Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.41009","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41009","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41009","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T13:11:44Z","timestamp":1759929104000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,11]]},"references-count":52,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019,11]]}},"alternative-id":["10.1002\/art.41009"],"URL":"https:\/\/doi.org\/10.1002\/art.41009","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,11]]},"assertion":[{"value":"2019-01-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}