Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition
Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafi...
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doaj-d3b25b0da38d434c9b4bf8efaa04055a2021-03-13T00:06:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01222894289410.3390/ijms22062894Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 InhibitionClarissa Corinaldesi0Rebecca L. Ross1Giuseppina Abignano2Cristina Antinozzi3Francesco Marampon4Luigi di Luigi5Maya H Buch6Valeria Riccieri7Andrea Lenzi8Clara Crescioli9Francesco Del Galdo10Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UKLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UKLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UKDepartment of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, ItalyDepartment of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, ItalyDepartment of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, ItalyLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UKDepartment of Internal medicine and Medical Specialties, University Sapienza, 00185 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, 00185 Rome, ItalyDepartment of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, ItalyLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UKSkeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. <i>In vitro</i>, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.https://www.mdpi.com/1422-0067/22/6/2894CXCL10sildenafilsystemic sclerosismyocytesinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Clarissa Corinaldesi Rebecca L. Ross Giuseppina Abignano Cristina Antinozzi Francesco Marampon Luigi di Luigi Maya H Buch Valeria Riccieri Andrea Lenzi Clara Crescioli Francesco Del Galdo |
spellingShingle |
Clarissa Corinaldesi Rebecca L. Ross Giuseppina Abignano Cristina Antinozzi Francesco Marampon Luigi di Luigi Maya H Buch Valeria Riccieri Andrea Lenzi Clara Crescioli Francesco Del Galdo Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition International Journal of Molecular Sciences CXCL10 sildenafil systemic sclerosis myocytes inflammation |
author_facet |
Clarissa Corinaldesi Rebecca L. Ross Giuseppina Abignano Cristina Antinozzi Francesco Marampon Luigi di Luigi Maya H Buch Valeria Riccieri Andrea Lenzi Clara Crescioli Francesco Del Galdo |
author_sort |
Clarissa Corinaldesi |
title |
Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition |
title_short |
Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition |
title_full |
Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition |
title_fullStr |
Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition |
title_full_unstemmed |
Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition |
title_sort |
muscle damage in systemic sclerosis and cxcl10: the potential therapeutic role of pde5 inhibition |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-03-01 |
description |
Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. <i>In vitro</i>, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc. |
topic |
CXCL10 sildenafil systemic sclerosis myocytes inflammation |
url |
https://www.mdpi.com/1422-0067/22/6/2894 |
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