{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:28:18Z","timestamp":1790137698508,"version":"4.0.1"},"reference-count":43,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T00:00:00Z","timestamp":1480291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["K08-AR-062592"],"award-info":[{"award-number":["K08-AR-062592"]}]},{"name":"NIH","award":["R01-HL-095732"],"award-info":[{"award-number":["R01-HL-095732"]}]},{"DOI":"10.13039\/100001844","name":"Scleroderma Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001844","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Scleroderma Research Foundation grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA\u2010producing enzyme autotaxin (ATX), and to connect the ATX\/LPA and interleukin\u20106 (IL\u20106) pathways in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the effect of a novel ATX inhibitor, PAT\u2010048, on fibrosis and IL\u20106 expression in the mouse model of bleomycin\u2010induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA\u2010induced expression of IL\u20106, and IL\u20106\u2013induced expression of ATX. We next evaluated whether LPA\u2010induced ATX expression is dependent on IL\u20106, and whether baseline IL\u20106 expression in fibroblasts from SSc patients is dependent on ATX. Finally, we compared ATX and IL\u20106 expression in the skin of patients with SSc and healthy control subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PAT\u2010048 markedly attenuated bleomycin\u2010induced dermal fibrosis when treatment was initiated before or after the development of fibrosis. LPA stimulated expression of IL\u20106 in human dermal fibroblasts, and IL\u20106 stimulated fibroblast expression of ATX, connecting the ATX\/LPA and IL\u20106 pathways in an amplification loop. IL\u20106 knockdown abrogated LPA\u2010induced ATX expression in fibroblasts, and ATX inhibition attenuated IL\u20106 expression in fibroblasts and the skin of bleomycin\u2010challenged mice. Expression of both ATX and IL\u20106 was increased in SSc skin, and LPA\u2010induced IL\u20106 levels and IL\u20106\u2013induced ATX levels were increased in fibroblasts from SSc patients compared with controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ATX is required for the development and maintenance of dermal fibrosis in a mouse model of bleomycin\u2010induced SSc and enables 2 major mediators of SSc fibrogenesis, LPA and IL\u20106, to amplify the production of each other. Our results suggest that concurrent inhibition of these 2 pathways may be an effective therapeutic strategy for dermal fibrosis in SSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39797","type":"journal-article","created":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T11:18:53Z","timestamp":1467890333000},"page":"2964-2974","source":"Crossref","is-referenced-by-count":96,"title":["An Autotaxin\/Lysophosphatidic Acid\/Interleukin\u20106 Amplification Loop Drives Scleroderma Fibrosis"],"prefix":"10.1002","volume":"68","author":[{"given":"Flavia V.","family":"Castelino","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Bain","sequence":"additional","affiliation":[{"name":"PharmAkea San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica A.","family":"Pace","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine E.","family":"Black","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leaya","family":"George","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens K.","family":"Probst","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance","family":"Goulet","sequence":"additional","affiliation":[{"name":"PharmAkea San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Boston University Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Tager","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,11,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30262"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23855.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.6.168"},{"key":"e_1_2_7_5_1","first-page":"1281","article-title":"Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis","volume":"22","author":"Clements P","year":"1995","journal-title":"J Rheumatol"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780401110"},{"key":"e_1_2_7_7_1","first-page":"S387","article-title":"SAR100842, an antagonist of lysophaphatidic acid receptor 1, as a potential treatment for patients with systemic sclerosis: results from a phase 2a study [abstract]","volume":"66","author":"Khanna D","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.010909.105753"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2008.06.005"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2011.01395.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M605142200"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.02419-05"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mcg.0000225642.90898.0e"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0004OC"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027851"},{"key":"e_1_2_7_16_1","first-page":"1207","article-title":"Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma","volume":"19","author":"Feghali CA","year":"1992","journal-title":"J Rheumatol"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-010-1610-4"},{"key":"e_1_2_7_18_1","first-page":"S386","article-title":"Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis: week 24 data from a phase 2\/3 trial [abstract]","volume":"66","author":"Khanna D","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200422123"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2006.10.009"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1685"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2004-0175OC"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200204026"},{"key":"e_1_2_7_25_1","volume-title":"Patent: autotaxin inhibitors and uses thereof","author":"Amira Pharmaceuticals","year":"2012"},{"key":"e_1_2_7_26_1","first-page":"585","article-title":"Smooth muscle differentiation in scleroderma fibroblastic cells","volume":"137","author":"Sappino AP","year":"1990","journal-title":"Am J Pathol"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22186"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070112"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200955"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4672"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0802397"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.09.013"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80334-9"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302470"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90438-8"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2010.10.007"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.140"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.154"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2013.04.010"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M014985"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38990"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002696"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39658"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(14)70232-2"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39797","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39797","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.39797","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T14:56:10Z","timestamp":1759935370000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.39797"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,28]]},"references-count":43,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1002\/art.39797"],"URL":"https:\/\/doi.org\/10.1002\/art.39797","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,28]]}}}