CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFß.
Biochim Biophys Acta
; 1851(2): 194-202, 2015 Feb.
Article
en En
| MEDLINE
| ID: mdl-25457224
ABSTRACT
The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGFß) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins α-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P3 signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P3 became the S1P receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGFß-dependent up-regulation of SK1/S1P3 signaling axis and strongly reduced the profibrotic effect exerted by TGFß, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGFß challenge in the transmission of at least part of its profibrotic effect. These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P3 axis plays a critical role in the onset of fibrotic cell phenotype.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Fosfotransferasas (Aceptor de Grupo Alcohol)
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Mioblastos Esqueléticos
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Receptores de Lisoesfingolípidos
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Factor de Crecimiento Transformador beta1
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Transdiferenciación Celular
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Factor de Crecimiento del Tejido Conjuntivo
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Miofibroblastos
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2015
Tipo del documento:
Article
País de afiliación:
Italia