TY  - JOUR
A1  - Bruno, Gennaro
A1  - Cencetti, Francesca
A1  - Pertici, Irene
A1  - Japtok, Lukasz
A1  - Bernacchioni, Caterina
A1  - Donati, Chiara
A1  - Bruni, Paola
T1  - CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P(3) signaling axis: Implications in the action mechanism of TGF beta
JF  - Biochimica et biophysica acta : Molecular and cell biology of lipids
N2  - 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 (TGF beta) 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 alpha-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/S1P(3) signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P(3) became the SIP 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 TGF beta-dependent up-regulation of SKI/S1P(3) signaling axis and strongly reduced the profibrotic effect exerted by TGF beta, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGF beta 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/S1P(3) axis plays a critical role in the onset of fibrotic cell phenotype. (C) 2014 Elsevier B.V. All rights reserved.
KW  - Sphingosine kinase
KW  - S1P(3) receptor
KW  - Connective tissue growth factor
KW  - Myoblasts
KW  - Transforming growth factor beta
Y1  - 2015
U6  - https://doi.org/10.1016/j.bbalip.2014.11.011
SN  - 1388-1981
SN  - 0006-3002
VL  - 1851
IS  - 2
SP  - 194
EP  - 202
PB  - Elsevier
CY  - Amsterdam
ER  -