Gene regulation by mechanotransduction in fibroblasts.
Mechanical forces are important for connective tissue homeostasis. How do fibroblasts sense mechanical stress and how do they translate this information into an adaptive remodeling of the extracellular matrix (ECM)? Tenascin-C is rapidly induced in vivo by loading muscles and in vitro by stretching fibroblasts. Regulation of tenascin-C expression by mechanical signals occurs at the transcriptional level. Integrin receptors physically link the ECM to the cytoskeleton and act as force transducers: intracellular signals are triggered when integrins engage with ECM, and later when forces are applied. We found that cyclic strain does not induce tenascin-C messenger ribonucleic acid (mRNA) in fibroblasts lacking the beta1-integrin chain. An important link in integrin-dependent mechanotransduction is the small guanosine 5'-triphosphatase. RhoA and its target kinase, ROCK. In fibroblasts, cyclic strain activates RhoA and thereby induces ROCK-dependent actin assembly. Interestingly, tenascin-C mRNA induction by cyclic strain was suppressed by relaxing the cytoskeleton with a ROCK inhibitor or by actin depolymerization. Conversely, chemical activators of RhoA enhanced the effect of strain both on actin dynamics and on tenascin-C expression. Thus, RhoA/ROCK-controlled actin dynamics are required for the induction of specific ECM genes by mechanical stress. These findings have implications for the understanding of regeneration and for tissue engineering.
Chiquet
Matthias
M
ITI Research Institute for Dental and Skeletal Biology, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland. matthias.chiquet@fmi.ch
Tunç-Civelek
Vildan
V
Sarasa-Renedo
Ana
A
D000818:Animals; D003238:Connective Tissue / Q000378:metabolism; D015444:Exercise; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*