{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:01:48Z","timestamp":1788483708313,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T00:00:00Z","timestamp":1577404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB CRC1181 (project C01) and SFB TR221 (B04)"],"award-info":[{"award-number":["SFB CRC1181 (project C01) and SFB TR221 (B04)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SO 1735\/2\u20101, DI 1537\/7\u20101, DI 1537\/8\u20101, DI 1537\/9\u20101"],"award-info":[{"award-number":["SO 1735\/2\u20101, DI 1537\/7\u20101, DI 1537\/8\u20101, DI 1537\/9\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"\n Objective<\/jats:title>\n \n Expression of dipeptidylpeptidase 4 (\n DPP<\/jats:styled-content>\n \u20104) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of\n DDP<\/jats:styled-content>\n \u20104 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate\n DPP<\/jats:styled-content>\n \u20104 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (\n SS<\/jats:styled-content>\n c).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Expression of\n DPP<\/jats:styled-content>\n \u20104 in skin biopsy samples and dermal fibroblasts was analyzed by real\u2010time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of\n DPP<\/jats:styled-content>\n \u20104 was modulated by overexpression, knockdown, and pharmacologic inhibition of\n DPP<\/jats:styled-content>\n 4 using sitagliptin and vildagliptin. The effects of\n DPP<\/jats:styled-content>\n 4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of\n SS<\/jats:styled-content>\n c (each n = 6).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The expression of\n DPP<\/jats:styled-content>\n \u20104 and the number of\n DPP<\/jats:styled-content>\n \u20104\u2013positive fibroblasts were increased in the fibrotic skin of\n SS<\/jats:styled-content>\n c patients, in a transforming growth factor \u03b2 (\n TGF<\/jats:styled-content>\n \u03b2)\u2013dependent manner.\n DPP<\/jats:styled-content>\n \u20104\u2013positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each\n P<\/jats:italic>\n < 0.001 versus healthy controls). Overexpression of\n DPP<\/jats:styled-content>\n 4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of\n DPP<\/jats:styled-content>\n 4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each\n P<\/jats:italic>\n < 0.001 versus control mice) by interfering with\n TGF<\/jats:styled-content>\n \u03b2\u2010induced\n ERK<\/jats:styled-content>\n signaling.\n DPP<\/jats:styled-content>\n 4\u2010knockout mice were less sensitive to bleomycin\u2010induced dermal and pulmonary fibrosis (\n P<\/jats:italic>\n < 0.0001 versus wild\u2010type controls). Treatment with\n DPP<\/jats:styled-content>\n 4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft\u2010versus\u2010host disease, and ameliorated fibrosis in\n TSK<\/jats:styled-content>\n 1 mice (each\n P<\/jats:italic>\n < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n DPP<\/jats:styled-content>\n \u20104 characterizes a population of activated fibroblasts and shows that\n DPP<\/jats:styled-content>\n \u20104 regulates\n TGF<\/jats:styled-content>\n \u03b2\u2010induced fibroblast activation in the fibrotic skin of\n SS<\/jats:styled-content>\n c patients. Inhibition of\n DPP<\/jats:styled-content>\n 4 exerts potent antifibrotic effects when administered in well\u2010tolerated doses. As\n DPP<\/jats:styled-content>\n 4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with\n SS<\/jats:styled-content>\n c.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41058","type":"journal-article","created":{"date-parts":[[2019,7,27]],"date-time":"2019-07-27T02:28:33Z","timestamp":1564194513000},"page":"137-149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":112,"title":["Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3881-2325","authenticated-orcid":false,"given":"Alina","family":"Soare","sequence":"first","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen, Erlangen, Germany, and Davila University of Medicine and Pharmacy Bucharest Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermina A.","family":"Gy\u00f6rfi","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3145","authenticated-orcid":false,"given":"Alexandru E.","family":"Matei","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dees","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Rauber","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wohlfahrt","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Ludolph","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymund E.","family":"Horch","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"B\u00e4uerle","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"von H\u00f6rsten","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Mihai","sequence":"additional","affiliation":[{"name":"University Hospital Zurich, Zurich, Switzerland, and Carol Davila University of Medicine and Pharmacy Bucharest Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2413-1959","authenticated-orcid":false,"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[{"name":"University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ramming","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8740-9615","authenticated-orcid":false,"given":"Georg","family":"Schett","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010Nuremberg and Universit\u00e4tsklinikum Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-9333","authenticated-orcid":false,"given":"J\u00f6rg H. 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