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Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation

Dupuytren’s disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients’ daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-β1. But,...

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Autores principales: Oezel, Lisa, Wohltmann, Marie, Gondorf, Nele, Wille, Julia, Güven, Irmak, Windolf, Joachim, Thelen, Simon, Jaekel, Carina, Grotheer, Vera
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606262/
https://www.ncbi.nlm.nih.gov/pubmed/37894778
http://dx.doi.org/10.3390/ijms242015097
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author Oezel, Lisa
Wohltmann, Marie
Gondorf, Nele
Wille, Julia
Güven, Irmak
Windolf, Joachim
Thelen, Simon
Jaekel, Carina
Grotheer, Vera
author_facet Oezel, Lisa
Wohltmann, Marie
Gondorf, Nele
Wille, Julia
Güven, Irmak
Windolf, Joachim
Thelen, Simon
Jaekel, Carina
Grotheer, Vera
author_sort Oezel, Lisa
collection PubMed
description Dupuytren’s disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients’ daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-β1. But, the extent to which impaired TGF-β1 release or TGF-β signal degradation is involved in pathologically altered myofibroblastogenesis in DD has been barely examined. Therefore, the complex in which TGF-β1 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-β1 activation, were herein analyzed in DD-fibroblasts (DD-FBs). Additionally, TGF-β 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, 𝛼-smooth-muscle-actin (𝛼-SMA) expression was evaluated. It was demonstrated that latency-associated peptide (LAP)-TGF-β and latent TGF-β-binding protein (LTBP)-1 involved in TGF-β-complex building were significantly upregulated in DD. Plasmin a serinprotease responsible for the TGF-β release was significantly downregulated. The application of exogenous plasmin was able to inhibit disturbed myofibroblastogenesis, as measured via 𝛼-SMA expression. Furthermore, a reduced TGF-β1 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-β1 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.
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spelling pubmed-106062622023-10-28 Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation Oezel, Lisa Wohltmann, Marie Gondorf, Nele Wille, Julia Güven, Irmak Windolf, Joachim Thelen, Simon Jaekel, Carina Grotheer, Vera Int J Mol Sci Article Dupuytren’s disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients’ daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-β1. But, the extent to which impaired TGF-β1 release or TGF-β signal degradation is involved in pathologically altered myofibroblastogenesis in DD has been barely examined. Therefore, the complex in which TGF-β1 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-β1 activation, were herein analyzed in DD-fibroblasts (DD-FBs). Additionally, TGF-β 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, 𝛼-smooth-muscle-actin (𝛼-SMA) expression was evaluated. It was demonstrated that latency-associated peptide (LAP)-TGF-β and latent TGF-β-binding protein (LTBP)-1 involved in TGF-β-complex building were significantly upregulated in DD. Plasmin a serinprotease responsible for the TGF-β release was significantly downregulated. The application of exogenous plasmin was able to inhibit disturbed myofibroblastogenesis, as measured via 𝛼-SMA expression. Furthermore, a reduced TGF-β1 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-β1 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. MDPI 2023-10-11 /pmc/articles/PMC10606262/ /pubmed/37894778 http://dx.doi.org/10.3390/ijms242015097 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Oezel, Lisa
Wohltmann, Marie
Gondorf, Nele
Wille, Julia
Güven, Irmak
Windolf, Joachim
Thelen, Simon
Jaekel, Carina
Grotheer, Vera
Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title_full Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title_fullStr Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title_full_unstemmed Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title_short Dupuytren’s Disease Is Mediated by Insufficient TGF-β1 Release and Degradation
title_sort dupuytren’s disease is mediated by insufficient tgf-β1 release and degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606262/
https://www.ncbi.nlm.nih.gov/pubmed/37894778
http://dx.doi.org/10.3390/ijms242015097
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