Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-beta1.
The fibrogenic differentiation of resident mesenchymal cells is a key parameter in the pathogenesis of radiation fibrosis and is triggered by the profibrotic growth factors transforming growth factor (TGF)-beta1 and CCN2. TGF-beta1 is considered the primary inducer of fibrogenic differentiation and is thought to control its long-term maintenance, whereas CCN2 is considered secondary effector of TGF-beta1. Yet, in long-term established fibrosis like that associated with delayed radiation enteropathy, in situ TGF-beta1 deposition is low, whereas CCN2 expression is high. To explore this apparent paradox, cell response to increasing doses of TGF-beta1 was investigated in cells modeling initiation and maintenance of fibrosis, i.e., normal and fibrosis-derived smooth muscle cells, respectively. Activation of cell-specific signaling pathways by low TGF-beta1 doses was demonstrated with a main activation of the Rho/ROCK pathway in fibrosis-derived cells, whereas the Smad pathway was mainly activated in normal cells. This leads to subsequent and cell-specific regulation of the CCN2 gene. These results suggested a specific profibrotic role of CCN2 in fibrosis-initiated cells. Furthermore, the modulation of CCN2 expression by itself and the combination of TGF-beta1 and CCN2 was investigated in fibrosis-derived cells. In fibrosis-initiated cells CCN2 triggered its autoinduction; furthermore, low concentration of TGF-beta1-potentiated CCN2 autoinduction. Our findings showed a differential requirement and action of TGF-beta1 in the fibrogenic response of normal vs. fibrosis-derived cells. This study defines a novel Rho/ROCK but Smad3-independent mode of TGF-beta signaling that may operate during the chronic stages of fibrosis and provides evidence of both specific and combinatorial roles of low TGF-beta1 dose and CCN2.
Haydont
Valérie
V
UPRES EA-27-10, Radiosensibilité des tumeurs et tissus sains, Institut de Radioprotection et de Sûreté Nucléaire/Institut Gustave Roussy, Villejuif, France.
Riser
Bruce L
BL
Aigueperse
Jocelyne
J
Vozenin-Brotons
Marie-Catherine
MC
D000368:Aged; D002454:Cell Differentiation / Q000528:radiation effects*; D002478:Cells, Cultured; D003106:Colon / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D055513:Connective Tissue Growth Factor; D004789:Enzyme Activation; D005355:Fibrosis; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D011832:Radiation Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011878:Radiotherapy / Q000009:adverse effects; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D051785:Smad Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D054460:rho-Associated Kinases