Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the <i>COL7A1</i> gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor...
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MDPI AG
2020-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/9/2108 |
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| author | Tania Aguado Marta García Adela García Gemma Ferrer-Mayorga Lucía Martínez-Santamaría Marcela del Río Luisa-María Botella José-María Sánchez-Puelles |
| author_facet | Tania Aguado Marta García Adela García Gemma Ferrer-Mayorga Lucía Martínez-Santamaría Marcela del Río Luisa-María Botella José-María Sánchez-Puelles |
| author_sort | Tania Aguado |
| collection | DOAJ |
| description | Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the <i>COL7A1</i> gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event. |
| first_indexed | 2024-03-10T16:17:48Z |
| format | Article |
| id | doaj.art-a7bae1e81a544c68a49d8af94b5b9af8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T16:17:48Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-a7bae1e81a544c68a49d8af94b5b9af82023-11-20T13:56:35ZengMDPI AGCells2073-44092020-09-0199210810.3390/cells9092108Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis BullosaTania Aguado0Marta García1Adela García2Gemma Ferrer-Mayorga3Lucía Martínez-Santamaría4Marcela del Río5Luisa-María Botella6José-María Sánchez-Puelles7Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, U-707 CIBERER, 28040 Madrid, SpainDepartament of Biomedical Engineering, Universidad Carlos III, 28911 Madrid, SpainDepartament of Biomedical Engineering, Universidad Carlos III, 28911 Madrid, SpainDepartment of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, SpainDepartament of Biomedical Engineering, Universidad Carlos III, 28911 Madrid, SpainDepartament of Biomedical Engineering, Universidad Carlos III, 28911 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, U-707 CIBERER, 28040 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, U-707 CIBERER, 28040 Madrid, SpainRecessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the <i>COL7A1</i> gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.https://www.mdpi.com/2073-4409/9/9/2108epidermolysis bullosaTGF-fibrosisraloxifeneN-acetylcysteineendoglinsmad |
| spellingShingle | Tania Aguado Marta García Adela García Gemma Ferrer-Mayorga Lucía Martínez-Santamaría Marcela del Río Luisa-María Botella José-María Sánchez-Puelles Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa Cells epidermolysis bullosa TGF-fibrosis raloxifene N-acetylcysteine endoglin smad |
| title | Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa |
| title_full | Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa |
| title_fullStr | Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa |
| title_full_unstemmed | Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa |
| title_short | Raloxifene and <span style="font-variant: small-caps">n</span>-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa |
| title_sort | raloxifene and span style font variant small caps n span acetylcysteine ameliorate tgf signalling in fibroblasts from patients with recessive dominant epidermolysis bullosa |
| topic | epidermolysis bullosa TGF-fibrosis raloxifene N-acetylcysteine endoglin smad |
| url | https://www.mdpi.com/2073-4409/9/9/2108 |
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