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There are two major dynamic processes in bone: bone formation and bone resorption which determine the volume of bone and ultimately its strength. Because bone is a tissue which is continuously remodeling, bone formation is an essential part of skeletal maintenance even after the growth period where bone formation is obviously essential. Moreover, bone has a remarkable regenerative potential which enables it to remodel itself in response to changing physical demands, and to repair itself after injury. In the majority of the adult skeleton, bone formation is confined to specific remodeling sites. Whether bone is lost or gained will depend on the extent of bone formation in each one of these sites. With regard to the mediators of bone formation, growth factors have received much attention. Of the several growth factors present in bone (IGF-I, IGF-II, TGF-β1, TGF-β2, PDGF, basic FGF, acidic FGF and BMPs), there is now sufficient evidence to document an important role for the IGFs in the local regulation of bone formation. In this paper we describe the components of the IGF regulatory system and discuss evidence supporting a role for IGFs in the local regulation of bone formation.

The fibroblast growth factors (FGFs) represent a family of peptide growth factors with relatively high amino acid sequence homologies ranging between 39 and 55% (Table 1; see Baird and Bohlen, 1990, for a review). The first two FGFs characterized, acidic and basic FGF (aFGF and bFGF, respectively), occur in most mesenchymal and neuroectodermal tissues. Five other members of the FGF family were identified as proteins encoded by tumor oncogenes. They possess bFGF-like biological activities in terms of their mitogenic effects. Acidic and basic FGF including some N-terminal truncated forms exert similar biological functions, aFGF being 10–100 times less potent than bFGF.

The fibroblast growth factors (FGFs) comprise a family of at least nine structurally homologous polypeptides that are found in a variety of cells and tissues (Baird and Bohlen, 1990; Brem and Klagsbrun, 1993; Burgess and Maciag, 1989; Folkman and Klagsbrun, 1987; Klagsbrun, 1989; Klagsbrun and D’Amore, 1991; Klagsbrun and Folkman, 1990; Rifkin and Moscatelli, 1989; Tanaka et al., 1992; Miyamoto et al., 1993). This family includes acidic FGF (aFGF), basic FGF (bFGF), int-2 protein, HST/K-FGF, FGF-5, FGF-6, keratinocyte growth factor (KGF), androgen-induced growth factor (AIGF), and glia-activating factor (GAF) (see Table I). These growth factors have been enumerated as FGF-1 through FGF-9, respectively, in order to simplify the nomenclature (Baird and Klagsbrun, 1991). However, since the name KGF is still widely used, the designation “KGF/FGF-7” will be used here in referring to this factor. The aFGF (FGF-1) and bFGF (FGF-2) proteins are the most extensively characterized FGF family members in terms of detailed knowledge concerning structure and biological activity.

Fibroblast growth factor (FGF) was first described by Gospodarowicz and co-workers as an activity derived from bovine brain or pituitary tissue (Gospodarowicz, 1974). As the name suggests, FGF was found to be mitogenic for fibroblasts in culture as well as endothelial cells and several other types of mesoderm-derived cells. It was first believed that FGF resulted from the degradation of myelin basic protein (Westall et al., 1978), but this was later found not to be the case (Thomas et al., 1980). Further characterization of the activity revealed that the primary mitogen from brain was different than that isolated from pituitary. These two factors were named acidic and basic FGF because they had similar if not identical biologic activities but differed in their iso-electric points.