title: CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFβ.
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 (TGFβ) 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 TGFβ-dependent up-regulation of SK1/S1P3 signaling axis and strongly reduced the profibrotic effect exerted by TGFβ, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGFβ 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.
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Bruno
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cencetti
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Pertici
authors.affiliation: Faculty of Mathematics and Natural Science, Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Arthur-Scheunert Allee 114-116, Nuthetal, Potsdam 14558, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bernacchioni
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Donati
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy. Electronic address: paola.bruni@unifi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Bruni
mesh_terms: D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D051379:Mice; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D055513:Connective Tissue Growth Factor; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; D000081025:Sphingosine-1-Phosphate Receptors; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C526318:CCN2 protein, mouse; C501285:S1pr3 protein, mouse
keywords: Connective tissue growth factor; Myoblasts; S1P(3) receptor; Sphingosine kinase; Transforming growth factor beta