Mechanical stress is required for high-level expression of connective tissue growth factor.
We used gene array technology to analyze differences in gene expression between mechanically stressed and relaxed fibroblasts. A number of stress-responsive genes that showed a two- to sixfold difference in their relative expression were identified. Connective tissue growth factor (CTGF) was among those genes that showed the most striking up-regulation by mechanical stress. Its regulation occurred at the transcriptional level and was reversible. A new steady state level of CTGF mRNA was reached within less than 6 h after stress relaxation. Mechanical stress was absolutely required for sustained high-level expression; TGF-beta, which is also known to stimulate CTGF synthesis, was not sufficient on its own. Experiments with specific inhibitors suggested that a protein kinase and a tyrosine phosphatase were involved in the transduction of the mechanical stimulus to gene expression. Since CTGF controls the synthesis of several extracellular matrix proteins, it is likely that this growth factor is responsible for the increased synthesis of collagen I and other matrix proteins in stressed fibroblasts.
Schild
Christof
C
M.E. Müller Institute for Biomechanics, University of Bern, Bern, CH-3010, Switzerland.
Trueb
Beat
B
D002460:Cell Line; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526317:CCN2 protein, human; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP; D011494:Protein Kinases; D017027:Protein Tyrosine Phosphatases