ABSTRACT
INTRODUCTION Growth factors are a large class of extracellular proteins that regulate nearly all aspects of cell function. While they were originally defined on the basis of their ability to stimulate the growth of cells, it has become clear that their range of activities is much broader and includes the ability to regulate cell survival, differentiation, movement, metabolic state, and biosynthesis. With the original discovery of growth factors by Rita Levi-Montalcini and Stanley Cohen in the 1950s came the prospects of using these small proteins to stimulate the repair and regeneration of injured tissues and organs in humans. After half a century, and with the discovery of well over one hundred growth factors, the great clinical potential for growth factor therapies remains unrealized. Indeed, the development of growth factor therapies has been met with the sobering reality that their potent activities in well-controlled in vitro systems do not often translate smoothly to the more complex in vivo setting. Thus, most large-scale growth factor clinical trials have produced disappointing outcomes (1,2). While there remains considerable excitement for the potential wide clinical use of growth factors, it has become clear that the complex mechanisms in place controlling growth factor activity need to be understood to design effective means of administration. In particular, it has become clear that a large number of growth factors are controlled locally within tissues by interactions with components of the extracellular matrix (ECM) (3-7). Consequently, this chapter will focus on the subclass of growth factors that bind to the ECM, will review the mechanisms that lead to their deposition and release from the ECM, and will discuss the consequences on growth factor pharmacokinetics, pharmacodynamics, and metabolism (Fig. 1). Unfortunately, the magnitude of this field of research and the space limitations of this chapter will prevent us from comprehensively citing many of the primary references for the findings that are described.
