Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development.

Although specific details may vary from system to system, some general concepts have emerged from studies of the regulation of ECM components, proteases, and protease inhibitors by growth factors. Growth factors may be divided into those that enhance matrix synthesis and inhibit matrix degradation and those that stimulate protease production and result in a general degradation of ECM. These relationships are illustrated in Fig. 3. In general, growth factors such as EGF, PDGF, bFGF, and IL-1 induce genes for ECM-degrading proteinases and their activators (e.g., metalloproteinases and PAs). This concerted release of proteases results in the degradation of the many components of basement membranes or ECM. Other growth factors (e.g., the TGF-beta family) stimulate the synthesis of ECM structural proteins (e.g., collagens and fibronectin), elevate levels of inhibitors of proteases (e.g., TIMP and PAI-1), and repress expression of the matrix-degrading metalloproteinases and PA. The overall result is systems in which such a relationship seems very likely. Direct evidence should become available within the next few years now that the technology exists to correlate spatial and temporal expression of growth factors with expression of ECM-associated proteases and inhibitors and to misregulate this expression in specific ways, for example, in transgenic mice. Future studies involving the use of model systems in which complex tissue interactions and organogenesis can be followed in culture should also provide the opportunity to examine cause-and-effect relationships between growth factors and ECM-modulating proteins.