Systemic mesalazine treatment prevents spontaneous skin fibrosis in PLK2-deficient mice
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| Názov: | Systemic mesalazine treatment prevents spontaneous skin fibrosis in PLK2-deficient mice |
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| Autori: | Manja Newe, Theresa A. Kant, Maximilian Hoffmann, Johanna S. E. Rausch, Luise Winter, Karolina Künzel, Erik Klapproth, Claudia Günther, Stephan R. Künzel |
| Zdroj: | Naunyn Schmiedebergs Arch Pharmacol |
| Informácie o vydavateľovi: | Springer Science and Business Media LLC, 2021. |
| Rok vydania: | 2021 |
| Predmety: | Male, Mice, Knockout, 0301 basic medicine, 0303 health sciences, Anti-Inflammatory Agents, Non-Steroidal, Cell Differentiation, Fibroblasts, Protein Serine-Threonine Kinases, Fibrosis, 3. Good health, Disease Models, Animal, Mice, 03 medical and health sciences, Fibroblasts/pathology [MeSH], Cell Differentiation/drug effects [MeSH], Skin/drug effects [MeSH], Collagen, Skin/pathology [MeSH], Original Article, Collagen/metabolism [MeSH], Male [MeSH], Phenoconversion, Creatinine/blood [MeSH], Disease Models, Animal [MeSH], Skin, Female [MeSH], Fibroblasts/drug effects [MeSH], Protein Serine-Threonine Kinases/genetics [MeSH], Anti-Inflammatory Agents, Non-Steroidal/administration, Anti-Inflammatory Agents, Non-Steroidal/pharmacology [MeSH], Osteopontin/genetics [MeSH], Animals [MeSH], Cytoskeleton, Mice, Knockout [MeSH], Mesalamine/toxicity [MeSH], Myofibroblasts, Mice [MeSH], Fibrosis/prevention, Mesalamine/administration, Mesalamine/pharmacology [MeSH], Anti-Inflammatory Agents, Non-Steroidal/toxicity [MeSH], Creatinine, Animals, Female, Osteopontin, Mesalamine |
| Popis: | Skin fibrosis is a complex biological remodeling process occurring in disease like systemic sclerosis, morphea, or eosinophilic fasciitis. Since the knowledge about the underlying pathomechanisms is still incomplete, there is currently no therapy, which prevents or reverses skin fibrosis sufficiently. The present study investigates the role of polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of cutaneous fibrosis and demonstrates the antifibrotic effects of systemic mesalazine treatment in vivo. Isolated primary dermal fibroblasts of PLK2 wild-type (WT) and knockout (KO) mice were characterized invitro. Skin thickness and histoarchitecture were studied in paraffin-embedded skin sections. The effects of mesalazine treatment were examined in isolated fibroblasts and PLK2 KO mice, which were fed 100 µg/g mesalazine for 6 months via the drinking water. Compared to WT, PLK2 KO fibroblasts displayed higher spontaneous myofibroblast differentiation, reduced proliferation rates, and overexpression of the fibrotic cytokine OPN. Invitro, 72 h of treatment with 10 mmol/L mesalazine induced phenotype conversion in PLK2 KO fibroblasts and attenuated OPN expression by inhibiting ERK1/2. In vivo, dermal myofibroblast differentiation, collagen accumulation, and skin thickening were prevented by mesalazine in PLK2 KO. Plasma creatinine levels indicated good tolerability of systemic long-term mesalazine treatment. The current study reveals a spontaneous fibrotic skin phenotype and ERK1/2-dependent OPN overexpression in PLK2 KO mice. We provide experimental evidence for the antifibrotic effectiveness of systemic mesalazine treatment to prevent fibrosis of the skin, suggesting further investigation in experimental and clinical settings. |
| Druh dokumentu: | Article Other literature type |
| Jazyk: | English |
| ISSN: | 1432-1912 0028-1298 |
| DOI: | 10.1007/s00210-021-02135-w |
| Prístupová URL adresa: | https://link.springer.com/content/pdf/10.1007/s00210-021-02135-w.pdf https://pubmed.ncbi.nlm.nih.gov/34410453 https://link.springer.com/content/pdf/10.1007/s00210-021-02135-w.pdf https://link.springer.com/article/10.1007/s00210-021-02135-w https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514377 https://repository.publisso.de/resource/frl:6447999 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . |
| Prístupové číslo: | edsair.doi.dedup.....6fccc8e89a42e4da3681785c68cae716 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Skin fibrosis is a complex biological remodeling process occurring in disease like systemic sclerosis, morphea, or eosinophilic fasciitis. Since the knowledge about the underlying pathomechanisms is still incomplete, there is currently no therapy, which prevents or reverses skin fibrosis sufficiently. The present study investigates the role of polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of cutaneous fibrosis and demonstrates the antifibrotic effects of systemic mesalazine treatment in vivo. Isolated primary dermal fibroblasts of PLK2 wild-type (WT) and knockout (KO) mice were characterized invitro. Skin thickness and histoarchitecture were studied in paraffin-embedded skin sections. The effects of mesalazine treatment were examined in isolated fibroblasts and PLK2 KO mice, which were fed 100 µg/g mesalazine for 6 months via the drinking water. Compared to WT, PLK2 KO fibroblasts displayed higher spontaneous myofibroblast differentiation, reduced proliferation rates, and overexpression of the fibrotic cytokine OPN. Invitro, 72 h of treatment with 10 mmol/L mesalazine induced phenotype conversion in PLK2 KO fibroblasts and attenuated OPN expression by inhibiting ERK1/2. In vivo, dermal myofibroblast differentiation, collagen accumulation, and skin thickening were prevented by mesalazine in PLK2 KO. Plasma creatinine levels indicated good tolerability of systemic long-term mesalazine treatment. The current study reveals a spontaneous fibrotic skin phenotype and ERK1/2-dependent OPN overexpression in PLK2 KO mice. We provide experimental evidence for the antifibrotic effectiveness of systemic mesalazine treatment to prevent fibrosis of the skin, suggesting further investigation in experimental and clinical settings. |
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| ISSN: | 14321912 00281298 |
| DOI: | 10.1007/s00210-021-02135-w |