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Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis

BACKGROUND: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis. RESULTS: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 health...

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Autores principales: Usategui, Alicia, Municio, Cristina, Arias-Salgado, Elena G., Martín, María, Fernández-Varas, Beatriz, Del Rey, Manuel J., Carreira, Patricia, González, Antonio, Criado, Gabriel, Perona, Rosario, Pablos, José L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8793167/
https://www.ncbi.nlm.nih.gov/pubmed/35086525
http://dx.doi.org/10.1186/s12979-022-00263-2
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author Usategui, Alicia
Municio, Cristina
Arias-Salgado, Elena G.
Martín, María
Fernández-Varas, Beatriz
Del Rey, Manuel J.
Carreira, Patricia
González, Antonio
Criado, Gabriel
Perona, Rosario
Pablos, José L.
author_facet Usategui, Alicia
Municio, Cristina
Arias-Salgado, Elena G.
Martín, María
Fernández-Varas, Beatriz
Del Rey, Manuel J.
Carreira, Patricia
González, Antonio
Criado, Gabriel
Perona, Rosario
Pablos, José L.
author_sort Usategui, Alicia
collection PubMed
description BACKGROUND: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis. RESULTS: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients. To analyze the potential role of DNA damage in skin fibrosis, we evaluated the effects of the DNA protective GSE4 peptide in the bleomycin mouse model of scleroderma and the fibrotic response of cultured human dermal fibroblasts. Administration of GSE4-nanoparticles attenuated bleomycin-induced skin fibrosis as measured by Masson’s staining of collagen and reduced Acta2 and Ctgf mRNA expression, whereas transduction of dermal fibroblasts with a lentiviral GSE4 expression vector reduced COL1A1, ACTA2 and CTGF gene expression after stimulation with bleomycin or TGF-β, in parallel to a reduction of the phospho-histone H2A.X marker of DNA damage. CONCLUSIONS: SSc is associated with TS, particularly in patients with lung disease or anti-topoisomerase I antibodies. Administration of GSE4 peptide attenuated experimental skin fibrosis and reduced fibroblast expression of profibrotic factors, supporting a role for oxidative DNA damage in scleroderma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-022-00263-2.
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spelling pubmed-87931672022-02-03 Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis Usategui, Alicia Municio, Cristina Arias-Salgado, Elena G. Martín, María Fernández-Varas, Beatriz Del Rey, Manuel J. Carreira, Patricia González, Antonio Criado, Gabriel Perona, Rosario Pablos, José L. Immun Ageing Research BACKGROUND: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis. RESULTS: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients. To analyze the potential role of DNA damage in skin fibrosis, we evaluated the effects of the DNA protective GSE4 peptide in the bleomycin mouse model of scleroderma and the fibrotic response of cultured human dermal fibroblasts. Administration of GSE4-nanoparticles attenuated bleomycin-induced skin fibrosis as measured by Masson’s staining of collagen and reduced Acta2 and Ctgf mRNA expression, whereas transduction of dermal fibroblasts with a lentiviral GSE4 expression vector reduced COL1A1, ACTA2 and CTGF gene expression after stimulation with bleomycin or TGF-β, in parallel to a reduction of the phospho-histone H2A.X marker of DNA damage. CONCLUSIONS: SSc is associated with TS, particularly in patients with lung disease or anti-topoisomerase I antibodies. Administration of GSE4 peptide attenuated experimental skin fibrosis and reduced fibroblast expression of profibrotic factors, supporting a role for oxidative DNA damage in scleroderma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-022-00263-2. BioMed Central 2022-01-27 /pmc/articles/PMC8793167/ /pubmed/35086525 http://dx.doi.org/10.1186/s12979-022-00263-2 Text en © The Author(s) 2022 https://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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Usategui, Alicia
Municio, Cristina
Arias-Salgado, Elena G.
Martín, María
Fernández-Varas, Beatriz
Del Rey, Manuel J.
Carreira, Patricia
González, Antonio
Criado, Gabriel
Perona, Rosario
Pablos, José L.
Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title_full Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title_fullStr Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title_full_unstemmed Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title_short Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis
title_sort evidence of telomere attrition and a potential role for dna damage in systemic sclerosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8793167/
https://www.ncbi.nlm.nih.gov/pubmed/35086525
http://dx.doi.org/10.1186/s12979-022-00263-2
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