{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:42:28Z","timestamp":1784547748276,"version":"3.55.0"},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001677","name":"INSERM","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007586","name":"Aix-Marseille Universit\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016913","name":"MSDAVENIR","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016913","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":[[2022,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive fibrosis, immune dysfunction, and vascular damage, in which the expression of many growth factors is deregulated. CD146 was recently described as a major actor in SSc. Since CD146 also exists as a circulating soluble form (sCD146) that acts as a growth factor in numerous angiogenic\u2010 and inflammation\u2010related pathologies, we sought to identify the mechanisms underlying the generation of sCD146 and to characterize the regulation and functions of the different variants identified in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed in vitro experiments, including RNA\u2010Seq and antibody arrays, and in vivo experiments using animal models of bleomycin\u2010induced SSc and hind limb ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multiple forms of sCD146, generated by both shedding and alternative splicing of the primary transcript, were discovered. The shed form of sCD146 was generated from the cleavage of both long and short membrane isoforms of CD146 through ADAM\u201010 and TACE metalloproteinases, respectively. In addition, 2 novel sCD146 splice variants, I5\u201013\u2010sCD146 and I10\u2010sCD146, were identified. Of interest, I5\u201013\u2010sCD146 was significantly increased in the sera of SSc patients (<jats:italic>P<\/jats:italic> &lt; 0.001; n\u2009=\u2009117), in particular in patients with pulmonary fibrosis (<jats:italic>P<\/jats:italic> &lt; 0.01; n\u2009=\u2009112), whereas I10\u2010sCD146 was decreased (<jats:italic>P<\/jats:italic> &lt; 0.05; n\u2009=\u2009117). Further experiments revealed that shed sCD146 and I10\u2010sCD146 displayed proangiogenic activity through the focal adhesion kinase and protein kinase C\u03b5 signaling pathways, respectively, whereas I5\u201013\u2010sCD146 displayed profibrotic effects through the Wnt\u20101\/\u03b2\u2010catenin\/WISP\u20101 pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Variants of sCD146, and in particular the novel I5\u201013\u2010sCD146 splice variant, could constitute novel biomarkers and\/or molecular targets for the diagnosis and treatment of SSc and other angiogenesis\u2010 or fibrosis\u2010related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42063","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T21:59:07Z","timestamp":1641765547000},"page":"1027-1038","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Involvement of Multiple Variants of Soluble <scp>CD146<\/scp> in Systemic Sclerosis: Identification of a Novel Profibrotic Factor"],"prefix":"10.1002","volume":"74","author":[{"given":"Marie","family":"Nollet","sequence":"first","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0236-2633","authenticated-orcid":false,"given":"Richard","family":"Bachelier","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Joshkon","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wa\u00ebl","family":"Traboulsi","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amandine","family":"Mahieux","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anais","family":"Moyon","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN, and CERIMED, Aix\u2010Marseille University  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Muller","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indumathi","family":"Somasundaram","sequence":"additional","affiliation":[{"name":"D. 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Patil University  Kolhapur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Simoncini","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Peiretti","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie S.","family":"Leroyer","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Guillet","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN, and CERIMED, Aix\u2010Marseille University  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Granel","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN, and AP\u2010HM  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Dignat\u2010George","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Bardin","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandrine","family":"Foucault\u2010Bertaud","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0152-3893","authenticated-orcid":false,"given":"Marcel","family":"Blot\u2010Chabaud","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille University, INSERM 1263, INRAE 1260, C2VN  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/antib6040017"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-014-0047-y"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-406108"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.213827"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH02-11-0285"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.MIB.0000194181.46930.88"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.83"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.446518"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-229591"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.183251"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2009.06.012"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.135.6.1655"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.04.046"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH05-07-0499"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","unstructured":"XuJ.Preparation culture and immortalization of mouse embryonic fibroblasts. 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