Regulation of extracellular matrix gene expression by mechanical stress.

Extracellular matrix (ECM) is the substrate for cell adhesion, growth, and differentiation, and it provides mechanical support to tissues. It is well known that connective tissue cells adapt their ECM to changes in mechanical load, as seen, e.g. during bone remodeling or wound healing. A feedback mechanism must exist by which cells that sense mechanical stress via their substrate respond by an altered pattern of protein expression, and thus remodel the ECM to meet changing mechanical requirements. What signals are triggered in connective tissue cells by mechanical stress, and how do such stimuli affect the expression of specific ECM proteins? The evidence will be reviewed that integrins, the transmembrane adhesion and signaling receptors which physically link ECM to the cytoskeleton, might be key players in transducing mechanical signals, presumably via MAP kinase and NF-kappaB pathways. At the far end of the response, there is evidence for regulation at the level of gene transcription. For example, the production of tenascin-C and collagen XII, two ECM proteins typical of tendons and ligaments, is high in fibroblasts attached to a stretched collagen matrix, but suppressed in cells on a relaxed matrix. The response to a change in stretch is rapid and reversible, and is reflected on the mRNA level. Both the tenascin-C and the collagen XII gene promoters contain 'stretch-responsive' enhancer regions with similarity to 'shear stress response elements' in other genes. The precise signal pathways converging on these mechano-responsive enhancer elements remain to be elucidated.