{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:42:31Z","timestamp":1773769351980,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008728","name":"Japan Research Foundation for Clinical Pharmacology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008728","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["T32\u2010AR\u2010007080"],"award-info":[{"award-number":["T32\u2010AR\u2010007080"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01\u2010AI\u2010183620"],"award-info":[{"award-number":["R01\u2010AI\u2010183620"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R56\u2010AR076384"],"award-info":[{"award-number":["R56\u2010AR076384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019921","name":"National Scleroderma Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019921","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007270","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"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by the cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro\u2010inflammatory, pro\u2010arthritic, and pro\u2010angiogenic responses. In this study, we explored the antifibrotic potential of targeting the sCD13\u2010B1R axis in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression of CD13, B1R, and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of the genes for CD13, B1R, and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc) SSc. Notably, single\u2010cell analysis of SSc skin biopsies revealed the highest <jats:italic>BDKRB1<\/jats:italic> expression in <jats:italic>COL8A1<\/jats:italic>\u2010positive myofibroblasts, a population exclusively seen in SSc. Transforming growth factor beta (TGF\u03b2) induced the expression of <jats:italic>BDKRB1<\/jats:italic> and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The pro\u2010fibrotic responses of sCD13 or TGF\u03b2 were prevented by a B1R antagonist. Mice lacking <jats:italic>Cd13<\/jats:italic> or <jats:italic>Bdkrb1<\/jats:italic> were resistant to bleomycin\u2010induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis and suggest that targeting the sCD13\u2010B1R signaling axis is a promising novel therapeutic approach for SSc.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42973-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42973","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T23:54:11Z","timestamp":1724370851000},"page":"80-91","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Targeting CD13\/Aminopeptidase N as a Novel Therapeutic Approach for Scleroderma Fibrosis"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9853-8057","authenticated-orcid":false,"given":"Sei","family":"Muraoka","sequence":"first","affiliation":[{"name":"University of Michigan, Ann Arbor, and Toho University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Brodie","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1164-5176","authenticated-orcid":false,"given":"Megan N.","family":"Mattichak","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-1751","authenticated-orcid":false,"given":"Mikel","family":"Gurrea\u2010Rubio","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4091-8882","authenticated-orcid":false,"given":"Yuzo","family":"Ikari","sequence":"additional","affiliation":[{"name":"University of Michigan, Ann Arbor and Showa University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Foster","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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