How do fibroblasts translate mechanical signals into changes in extracellular matrix production?

Mechanical forces are important regulators of connective tissue homeostasis. Our recent experiments in vivo indicate that externally applied mechanical load can lead to the rapid and sequential induction of distinct extracellular matrix (ECM) components in fibroblasts, rather than to a generalized hypertrophic response. Thus, ECM composition seems to be adapted specifically to changes in load. Mechanical stress can regulate the production of ECM proteins indirectly, by stimulating the release of a paracrine growth factor, or directly, by triggering an intracellular signalling pathway that activates the gene. We have evidence that tenascin-C is an ECM component directly regulated by mechanical stress: induction of its mRNA in stretched fibroblasts is rapid both in vivo and in vitro, does not depend on prior protein synthesis, and is not mediated by factors released into the medium. Fibroblasts sense force-induced deformations (strains) in their ECM. Findings by other researchers indicate that integrins within cell-matrix adhesions can act as 'strain gauges', triggering MAPK and NF-kappaB pathways in response to changes in mechanical stress. Our results indicate that cytoskeletal 'pre-stress' is important for mechanotransduction to work: relaxation of the cytoskeleton (e.g. by inhibiting Rho-dependent kinase) suppresses induction of the tenascin-C gene by cyclic stretch, and hence desensitizes the fibroblasts to mechanical signals. On the level of the ECM genes, we identified related enhancer sequences that respond to static stretch in both the tenascin-C and the collagen XII promoter. In the case of the tenascin-C gene, different promoter elements might be involved in induction by cyclic stretch. Thus, different mechanical signals seem to regulate distinct ECM genes in complex ways.