{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T01:00:48Z","timestamp":1778720448336,"version":"3.51.4"},"reference-count":57,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T00:00:00Z","timestamp":1696982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dupuytren\u2019s disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients\u2019 daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-\u03b21. But, the extent to which impaired TGF-\u03b21 release or TGF-\u03b2 signal degradation is involved in pathologically altered myofibroblastogenesis in DD has been barely examined. Therefore, the complex in which TGF-\u03b21 is secreted in the extracellular matrix to elicit its biological activity, and proteins such as plasmin, integrins, and matrix metalloproteinases (MMPs), which are involved in the TGF-\u03b21 activation, were herein analyzed in DD-fibroblasts (DD-FBs). Additionally, TGF-\u03b2 signal degradation via caveolin-1 was examined with 5-fluoruracil (5-FU) in detail. Gene expression analysis was performed via Western blot, PCR, and immunofluorescence analyses. As a surrogate parameter for disturbed myofibroblastogenesis, \ud835\udefc-smooth-muscle-actin (\ud835\udefc-SMA) expression was evaluated. It was demonstrated that latency-associated peptide (LAP)-TGF-\u03b2 and latent TGF-\u03b2-binding protein (LTBP)-1 involved in TGF-\u03b2-complex building were significantly upregulated in DD. Plasmin a serinprotease responsible for the TGF-\u03b2 release was significantly downregulated. The application of exogenous plasmin was able to inhibit disturbed myofibroblastogenesis, as measured via \ud835\udefc-SMA expression. Furthermore, a reduced TGF-\u03b21 degradation was also involved in the pathological phenotype of DD, because caveolin-1 expression was significantly downregulated, and if rescued, myofibroblastogenesis was also inhibited. Therefore, our study demonstrates that a deficient release and degradation of TGF-\u03b21 are important players in the pathological phenotype of DD and should be addressed in future research studies to improve DD therapy or other related fibrotic conditions.<\/jats:p>","DOI":"10.3390\/ijms242015097","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T03:07:47Z","timestamp":1697080067000},"page":"15097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dupuytren\u2019s Disease Is Mediated by Insufficient TGF-\u03b21 Release and Degradation"],"prefix":"10.3390","volume":"24","author":[{"given":"Lisa","family":"Oezel","sequence":"first","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Wohltmann","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nele","family":"Gondorf","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Wille","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irmak","family":"G\u00fcven","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Windolf","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Thelen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-3861","authenticated-orcid":false,"given":"Carina","family":"Jaekel","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6034-9608","authenticated-orcid":false,"given":"Vera","family":"Grotheer","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11552-013-9563-0","article-title":"Dupuytren\u2019s disease: Current state of the art","volume":"9","author":"Henry","year":"2014","journal-title":"Hand"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jhsa.2005.09.018","article-title":"The heritability of Dupuytren\u2019s disease: Familial aggregation and its clinical significance","volume":"31","author":"Hindocha","year":"2006","journal-title":"J. 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