Growth Factorecm Interaction Models And Applications

The interaction of growth factors with the ECM can obviously impact growth factor distribution and activity in vivo. The original observation that many growth factors bind to heparin suggested that HS within the ECM might function as a storage depot for these potent growth-regulatory proteins (21,154,155). Moreover, as additional binding sites for growth factors within the ECM have been identified, it has become clear that the ECM would likely play a critical role in defining growth factor pharmacokinetics and pharmacodynamics. For the FGF family members, it appears that HS interactions constitute the major sites of interaction within the ECM. Indeed, several studies have confirmed that members of the FGF family are endogenously deposited within the basement membrane bound to HS (33,156-159). The interaction of FGFs and VEGF with

HS has also been demonstrated to protect these proteins against proteases and physical denaturation (160-163). Furthermore, ECM, containing stored growth factors, has been demonstrated to function as a prolonged source of active growth factor, suggesting that the extracellular matrices in vivo play important roles as reservoirs of active growth factor (22,155,164,165). Several studies have also demonstrated that degradation of HSPG, or ECM in general, by heparanase or inflammatory proteases can result in the release of active growth factor that might participate in the tissue response to injury (16,58,166-168). In a sense, the ECM may be viewed as an endogenous matrix that mediates the controlled release of growth factors. The clinical application of this regulated storage and release system has already begun to be realized with the development of synthetic hep-arin-based controlled drug delivery systems, which are currently being evaluated in humans (169-172).

The storage and release of growth factors from ECM are likely controlled at many levels. Obviously, alterations in the local synthesis and deposition of ECM components and growth factors would alter the dynamics of this process, indicating that the "stored" growth factors are not static but in constant dynamic equilibrium with matrix-binding sites (14,70,72,173). Consequently, changes in the structure and density of growth factor-binding sites within the ECM, for example, through the action of extracellular enzymes such as the 6-O sulfatases, heparanases, or matrix metalloproteases, could modulate the binding kinetics of growth factors to the resident HS chains and could alter the structure of HS-modulated proteins such as fibronectin, leading to changes in ECM-growth factor binding and release (174-178). In addition, the interactions of growth factors with HSPG within the ECM might also be modulated by changes in the extracellular environment. As a specific example of this type of process, VEGF binding to HS is dramatically stabilized at low pH, suggesting that VEGF deposition in ECM would be controlled by factors such as hypoxia, which lead to decreased local pH (43,44). Together, these myriad actions have been demonstrated to provide a means for the ECM to modulate the molecular transport of growth factors and, in turn, the formation of growth factor and morphogen gradients required for coordinated tissue development (51,177-181). An appreciation of how this physiological process can modulate growth factor action is needed as growth factor treatment regimes are designed.

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