{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T23:45:56Z","timestamp":1783035956266,"version":"3.54.6"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI183620"],"award-info":[{"award-number":["R01AI183620"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56AR076384"],"award-info":[{"award-number":["R56AR076384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI183620"],"award-info":[{"award-number":["R01AI183620"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The LEO Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"DOI":"10.1186\/s13075-025-03723-4","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T10:06:04Z","timestamp":1768039564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Soluble CD13 in systemic sclerosis: clinical observations and transcriptomic insights from peripheral blood"],"prefix":"10.1186","volume":"28","author":[{"given":"Yuzo","family":"Ikari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Rosek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"St Clair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Webber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramadan A.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Suen","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"3723_CR1","doi-asserted-by":"publisher","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","volume":"1","author":"Y Allanore","year":"2015","unstructured":"Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, Varga J. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002.","journal-title":"Nat Rev Dis Primers"},{"issue":"5","key":"3723_CR2","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1136\/annrheumdis-2018-213455","volume":"78","author":"W Wu","year":"2019","unstructured":"Wu W, Jordan S, Graf N, de Oliveira Pena J, Curram J, Allanore Y, Matucci-Cerinic M, Pope JE, Denton CP, Khanna D, et al. Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European scleroderma trials and research (EUSTAR) cohort. Ann Rheum Dis. 2019;78(5):648\u201356.","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"3723_CR3","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1002\/art.1780330828","volume":"33","author":"PJ Clements","year":"1990","unstructured":"Clements PJ, Lachenbruch PA, Ng SC, Simmons M, Sterz M, Furst DE. Skin score. A semiquantitative measure of cutaneous involvement that improves prediction of prognosis in systemic sclerosis. Arthritis Rheum. 1990;33(8):1256\u201363.","journal-title":"Arthritis Rheum"},{"issue":"12","key":"3723_CR4","doi-asserted-by":"publisher","first-page":"2828","DOI":"10.1002\/1529-0131(200112)44:12<2828::AID-ART470>3.0.CO;2-U","volume":"44","author":"VD Steen","year":"2001","unstructured":"Steen VD, Medsger TA Jr. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 2001;44(12):2828\u201335.","journal-title":"Arthritis Rheum"},{"issue":"3","key":"3723_CR5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.5152\/eurjrheumatol.2014.036","volume":"1","author":"T Kang","year":"2014","unstructured":"Kang T, Abignano G, Lettieri G, Wakefield RJ, Emery P, Del Galdo F. Skin imaging in systemic sclerosis. Eur J Rheumatol. 2014;1(3):111\u20136.","journal-title":"Eur J Rheumatol"},{"issue":"1","key":"3723_CR6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4049\/jimmunol.1900868","volume":"204","author":"C Lu","year":"2020","unstructured":"Lu C, Amin MA, Fox DA. CD13\/Aminopeptidase N is a potential therapeutic target for inflammatory disorders. J Immunol. 2020;204(1):3\u201311.","journal-title":"J Immunol"},{"issue":"1","key":"3723_CR7","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1006\/cimm.2000.1629","volume":"201","author":"AN Santos","year":"2000","unstructured":"Santos AN, Langner J, Herrmann M, Riemann D. Aminopeptidase N\/CD13 is directly linked to signal transduction pathways in monocytes. Cell Immunol. 2000;201(1):22\u201332.","journal-title":"Cell Immunol"},{"issue":"6","key":"3723_CR8","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1189\/jlb.1204714","volume":"77","author":"P Mina-Osorio","year":"2005","unstructured":"Mina-Osorio P, Ortega E. Aminopeptidase N (CD13) functionally interacts with FcgammaRs in human monocytes. J Leukoc Biol. 2005;77(6):1008\u201317.","journal-title":"J Leukoc Biol"},{"issue":"17","key":"3723_CR9","first-page":"3250","volume":"128","author":"M Nefla","year":"2015","unstructured":"Nefla M, Sudre L, Denat G, Priam S, Andre-Leroux G, Berenbaum F, Jacques C. The pro-inflammatory cytokine 14-3-3epsilon is a ligand of CD13 in cartilage. J Cell Sci. 2015;128(17):3250\u201362.","journal-title":"J Cell Sci"},{"issue":"Pt 17","key":"3723_CR10","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.1242\/jcs.069484","volume":"123","author":"A Ghaffari","year":"2010","unstructured":"Ghaffari A, Li Y, Kilani RT, Ghahary A. 14-3-3 Sigma associates with cell surface aminopeptidase N in the regulation of matrix metalloproteinase-1. J Cell Sci. 2010;123(Pt 17):2996\u20133005.","journal-title":"J Cell Sci"},{"issue":"9","key":"3723_CR11","doi-asserted-by":"publisher","first-page":"e0162008","DOI":"10.1371\/journal.pone.0162008","volume":"11","author":"RL Morgan","year":"2016","unstructured":"Morgan RL, Behbahani-Nejad N, Endres J, Amin MA, Lepore NJ, Du Y, Urquhart A, Chung KC, Fox DA. Localization, Shedding, regulation and function of aminopeptidase N\/CD13 on fibroblast like synoviocytes. PLoS ONE. 2016;11(9):e0162008.","journal-title":"PLoS ONE"},{"key":"3723_CR12","doi-asserted-by":"crossref","unstructured":"Tsou PS, Lu C, Gurrea-Rubio M, Muraoka S, Campbell PL, Wu Q, Model EN, Lind ME, Vichaikul S, Mattichak MN et al. Soluble CD13 induces inflammatory arthritis by activating the Bradykinin receptor B1. J Clin Invest. 2022;132(11):e151827.","DOI":"10.1172\/JCI151827"},{"issue":"1","key":"3723_CR13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1002\/art.38878","volume":"67","author":"R Morgan","year":"2015","unstructured":"Morgan R, Endres J, Behbahani-Nejad N, Phillips K, Ruth JH, Friday SC, Edhayan G, Lanigan T, Urquhart A, Chung KC, et al. Expression and function of aminopeptidase N\/CD13 produced by fibroblast-like synoviocytes in rheumatoid arthritis: role of CD13 in chemotaxis of cytokine-activated T cells independent of enzymatic activity. Arthritis Rheumatol. 2015;67(1):74\u201385.","journal-title":"Arthritis Rheumatol"},{"issue":"2","key":"3723_CR14","doi-asserted-by":"publisher","first-page":"360","DOI":"10.4049\/jimmunol.1801276","volume":"203","author":"Y Du","year":"2019","unstructured":"Du Y, Lu C, Morgan RL, Stinson WA, Campbell PL, Cealey E, Fu W, Lepore NJ, Hervoso JL, Cui H, et al. Angiogenic and arthritogenic properties of the soluble form of CD13. J Immunol. 2019;203(2):360\u20139.","journal-title":"J Immunol"},{"issue":"1","key":"3723_CR15","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1002\/art.42973","volume":"77","author":"S Muraoka","year":"2025","unstructured":"Muraoka S, Brodie WD, Mattichak MN, Gurrea-Rubio M, Ikari Y, Foster C, Amin MA, Khanna N, Amin H, Campbell PL, et al. Targeting CD13\/Aminopeptidase N as a novel therapeutic approach for scleroderma fibrosis. Arthritis Rheumatol. 2025;77(1):80\u201391.","journal-title":"Arthritis Rheumatol"},{"issue":"1","key":"3723_CR16","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1080\/09537104.2017.1406076","volume":"30","author":"RA Rigg","year":"2019","unstructured":"Rigg RA, Healy LD, Chu TT, Ngo ATP, Mitrugno A, Zilberman-Rudenko J, Aslan JE, Hinds MT, Vecchiarelli LD, Morgan TK, et al. Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. Platelets. 2019;30(1):126\u201335.","journal-title":"Platelets"},{"issue":"3","key":"3723_CR17","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.pharmthera.2009.05.004","volume":"123","author":"N Vergnolle","year":"2009","unstructured":"Vergnolle N. Protease-activated receptors as drug targets in inflammation and pain. Pharmacol Ther. 2009;123(3):292\u2013309.","journal-title":"Pharmacol Ther"},{"issue":"11","key":"3723_CR18","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1161\/ATVBAHA.123.320046","volume":"43","author":"TJ Barrett","year":"2023","unstructured":"Barrett TJ. Targeting PAR4 to reduce atherosclerosis. Arterioscler Thromb Vasc Biol. 2023;43(11):2179\u201382.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"3723_CR19","doi-asserted-by":"crossref","unstructured":"Rwibasira Rudinga G, Khan GJ, Kong Y. Protease-Activated Receptor 4 (PAR4): a promising target for antiplatelet therapy. Int J Mol Sci. 2018;19(2):573.","DOI":"10.3390\/ijms19020573"},{"issue":"8","key":"3723_CR20","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1161\/CIRCULATIONAHA.119.044340","volume":"142","author":"MA Kolpakov","year":"2020","unstructured":"Kolpakov MA, Guo X, Rafiq K, Vlasenko L, Hooshdaran B, Seqqat R, Wang T, Fan X, Tilley DG, Kostyak JC, et al. Loss of Protease-Activated receptor 4 prevents inflammation resolution and predisposes the heart to cardiac rupture after myocardial infarction. Circulation. 2020;142(8):758\u201375.","journal-title":"Circulation"},{"issue":"5","key":"3723_CR21","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1111\/sji.12033","volume":"77","author":"L Nieuwenhuizen","year":"2013","unstructured":"Nieuwenhuizen L, Falkenburg WJ, Schutgens RE, Roosendaal G, van Veghel K, Biesma DH, Lafeber FP. Stimulation of Naive monocytes and PBMCs with coagulation proteases results in thrombin-mediated and PAR-1-dependent cytokine release and cell proliferation in PBMCs only. Scand J Immunol. 2013;77(5):339\u201349.","journal-title":"Scand J Immunol"},{"key":"3723_CR22","doi-asserted-by":"crossref","unstructured":"Tsou PS, Ali RA, Lu C, Sule G, Carmona-Rivera C, Lucotti S, Ikari Y, Wu Q, Campbell PL, Gurrea-Rubio M et al. Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection. JCI Insight. 2025;10(9):e184975.","DOI":"10.1172\/jci.insight.184975"},{"issue":"11","key":"3723_CR23","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","volume":"72","author":"F van den Hoogen","year":"2013","unstructured":"van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr., Carreira PE, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747\u201355.","journal-title":"Ann Rheum Dis"},{"issue":"6","key":"3723_CR24","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1136\/annrheumdis-2021-221313","volume":"81","author":"S Assassi","year":"2022","unstructured":"Assassi S, Volkmann ER, Zheng WJ, Wang X, Wilhalme H, Lyons MA, Roth MD, Tashkin DP. Peripheral blood gene expression profiling shows predictive significance for response to mycophenolate in systemic sclerosis-related interstitial lung disease. Ann Rheum Dis. 2022;81(6):854\u201360.","journal-title":"Ann Rheum Dis"},{"issue":"9","key":"3723_CR25","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1136\/annrheumdis-2018-213031","volume":"77","author":"CP Denton","year":"2018","unstructured":"Denton CP, Ong VH, Xu S, Chen-Harris H, Modrusan Z, Lafyatis R, Khanna D, Jahreis A, Siegel J, Sornasse T. Therapeutic interleukin-6 Blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the fasscinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77(9):1362\u201371.","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"3723_CR26","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.1038\/cti.2013.2","volume":"2","author":"S O\u2019Reilly","year":"2013","unstructured":"O\u2019Reilly S, Cant R, Ciechomska M, van Laar JM. Interleukin-6: a new therapeutic target in systemic sclerosis? Clin Transl Immunol. 2013;2(4):e4.","journal-title":"Clin Transl Immunol"},{"issue":"4","key":"3723_CR27","doi-asserted-by":"publisher","first-page":"435","DOI":"10.3899\/jrheum.120725","volume":"40","author":"A De Lauretis","year":"2013","unstructured":"De Lauretis A, Sestini P, Pantelidis P, Hoyles R, Hansell DM, Goh NS, Zappala CJ, Visca D, Maher TM, Denton CP, et al. Serum Interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol. 2013;40(4):435\u201346.","journal-title":"J Rheumatol"},{"issue":"1","key":"3723_CR28","doi-asserted-by":"publisher","first-page":"4949","DOI":"10.1038\/s41467-025-60034-7","volume":"16","author":"H Shimagami","year":"2025","unstructured":"Shimagami H, Nishimura K, Matsushita H, Metsugi S, Kato Y, Kawasaki T, Tsujimoto K, Edahiro R, Itotagawa E, Naito M, et al. Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis. Nat Commun. 2025;16(1):4949.","journal-title":"Nat Commun"},{"issue":"13","key":"3723_CR29","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184(13):3573\u201387. e3529.","journal-title":"Cell"},{"issue":"5","key":"3723_CR30","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","volume":"126","author":"P Schober","year":"2018","unstructured":"Schober P, Boer C, Schwarte LA. Correlation coefficients: appropriate use and interpretation. Anesth Analgesia. 2018;126(5):1763\u20138.","journal-title":"Anesth Analgesia"},{"issue":"7","key":"3723_CR31","doi-asserted-by":"publisher","first-page":"2422","DOI":"10.1002\/art.22721","volume":"56","author":"L Shand","year":"2007","unstructured":"Shand L, Lunt M, Nihtyanova S, Hoseini M, Silman A, Black CM, Denton CP. Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum. 2007;56(7):2422\u201331.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"3723_CR32","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.rdc.2007.11.005","volume":"34","author":"SI Nihtyanova","year":"2008","unstructured":"Nihtyanova SI, Denton CP. Current approaches to the management of early active diffuse scleroderma skin disease. Rheum Dis Clin North Am. 2008;34(1):161\u201379. viii.","journal-title":"Rheum Dis Clin North Am"},{"issue":"10","key":"3723_CR33","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1136\/annrheumdis-2015-208024","volume":"75","author":"R Dobrota","year":"2016","unstructured":"Dobrota R, Maurer B, Graf N, Jordan S, Mihai C, Kowal-Bielecka O, Allanore Y, Distler O, coauthors E. Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis. 2016;75(10):1743\u20138.","journal-title":"Ann Rheum Dis"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-025-03723-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-025-03723-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-025-03723-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T15:20:01Z","timestamp":1770391201000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13075-025-03723-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,10]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3723"],"URL":"https:\/\/doi.org\/10.1186\/s13075-025-03723-4","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,10]]},"assertion":[{"value":"23 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study complied with all relevant ethical regulations and was approved by the University of Michigan Institutional Review Board; all participants provided informed consent for blood donation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30"}}