{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:07:02Z","timestamp":1782817622691,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T00:00:00Z","timestamp":1524441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008741","name":"European League Against Rheumatism","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008741","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":[[2018,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Aberrant activation of Wnt signaling has been observed in tissues from patients with systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c). This study aimed to determine the role of transforming growth factor \u03b2 (<jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2) in driving the increased Wnt signaling, through modulation of axis inhibition protein 2 (Axin\u20102), a critical regulator of the Wnt canonical pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Canonical Wnt signaling activation was analyzed by <jats:styled-content style=\"fixed-case\">TOP<\/jats:styled-content>flash T cell factor\/lymphoid enhancer factor promoter assays. Axin\u20102 was evaluated in\u00a0vitro by analysis of Axin\u20102 primary\/mature transcript expression and decay, <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2 receptor type I (<jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2<jats:styled-content style=\"fixed-case\">RI<\/jats:styled-content>) blockade, small interfering <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2013mediated depletion of tristetraprolin 1, and <jats:styled-content style=\"fixed-case\">XAV<\/jats:styled-content>\u2010939\u2013mediated Axin\u20102 stabilization. In vivo, Axin\u20102 messenger <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>) and protein expression was determined in skin and lung biopsy samples from mice that express a kinase\u2010deficient <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2<jats:styled-content style=\"fixed-case\">RII<\/jats:styled-content> specifically on fibroblasts (T\u03b2<jats:styled-content style=\"fixed-case\">RII<\/jats:styled-content>\u0394k\u2010fib\u2013transgenic mice) and from littermate controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts displayed an increased response to canonical Wnt ligands despite basal levels of Wnt signaling that were comparable to those in healthy control fibroblasts in\u00a0vitro. Notably, we showed that <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts had reduced basal expression of Axin\u20102, which was caused by an endogenous <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2\u2013dependent increase in Axin\u20102 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> decay. Accordingly, we observed that <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2 decreased Axin\u20102 expression both in\u00a0vitro in healthy control fibroblasts and in\u00a0vivo in T\u03b2<jats:styled-content style=\"fixed-case\">RII<\/jats:styled-content>\u0394k\u2010fib\u2013transgenic mice. Additionally, using Axin\u20102 gain\u2010 and loss\u2010of\u2010function experiments, we demonstrated that the <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2\u2010induced increased response to Wnt activation characteristic of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts depended on reduced bioavailability of Axin\u20102.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights the importance of reduced bioavailability of Axin\u20102 in mediating the increased canonical Wnt response observed in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt\/\u03b2\u2010catenin\u2013driven pathology and supports the rationale for targeting the <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2 pathway to regulate the aberrant Wnt signaling observed during fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40437","type":"journal-article","created":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T16:26:45Z","timestamp":1517934405000},"page":"932-942","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Transforming Growth Factor \u03b2 Activation Primes Canonical Wnt Signaling Through Down\u2010Regulation of Axin\u20102"],"prefix":"10.1002","volume":"70","author":[{"given":"Justin","family":"Gillespie","sequence":"first","affiliation":[{"name":"University of Leeds and Leeds Teaching Hospitals NHS Trust Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Ross","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Corinaldesi","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Esteves","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Derrett\u2010Smith","sequence":"additional","affiliation":[{"name":"University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"McDermott","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina M.","family":"Doody","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Denton","sequence":"additional","affiliation":[{"name":"University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Emery","sequence":"additional","affiliation":[{"name":"University of Leeds and Leeds Teaching Hospitals NHS Trust Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-2283","authenticated-orcid":false,"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[{"name":"University of Leeds and Leeds Teaching Hospitals NHS Trust Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,4,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005058"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.004077"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12874998"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-1273rev"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2009.26"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22328"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.318"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300636200"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23379"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34424"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200568"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64282-4"},{"key":"e_1_2_6_14_1","first-page":"7","article-title":"Role for \u03b13 integrin in EMT and pulmonary fibrosis","volume":"119","author":"Borok Z","year":"2009","journal-title":"J Clin Invest"},{"key":"e_1_2_6_15_1","first-page":"772","article-title":"WNT1\u2010inducible signalling protein\u20101 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis","volume":"119","author":"K\u00f6nigshoff M","year":"2009","journal-title":"J Clin Invest"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007898"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1427"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(98)70226-X"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00685-2"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.11.4371-4376.2005"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.4.1172-1183.2002"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200139200"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/141.1.321"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5363.596"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/386293"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1402.082"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1734"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098"},{"key":"e_1_2_6_29_1","first-page":"1573","article-title":"Criteria for the classification of early systemic sclerosis","volume":"28","author":"LeRoy EC","year":"2001","journal-title":"J Rheumatol"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2986"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.019"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304856200"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209645"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2013.192"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01020-13"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08356"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5701101"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002696"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30312"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202544"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.40437","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40437","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:11:02Z","timestamp":1759925462000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.40437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,23]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,6]]}},"alternative-id":["10.1002\/art.40437"],"URL":"https:\/\/doi.org\/10.1002\/art.40437","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,23]]},"assertion":[{"value":"2016-09-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-01-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}