In contrast to the restricted pattern characteristic of many of the FGFs, FGF-2 is expressed in many different tissues and cell types. It exerts a plethora of effects, both in vivo and in vitro, including mitogenic, chemotactic, angiogenic, and developmental activities. Thus, it is reported to act as a survival factor in many models of tissue repair, ranging from neural injury models to corneal and skin wounds (26). Surprisingly, considering the myriad of potential functions, mice lacking FGF-2 appeared superficially indistinguishable from wild-type littermates. However, when these mice were challenged by full-thickness excisional wounding, they showed delayed healing (27). In addition to a retardation in the rate of reepithelialization, mice null for FGF-2 show reduced collagen deposition at the wound site and also have thicker scabs. Expression of FGF-2 is known to be enhanced following injury (8,28), and topical application of FGF-2 has been reported to accelerate both dermal and epidermal repair (29-31). In addition, neutralizing antibodies to FGF-2 were shown to inhibit granulation tissue formation in sponges implanted into rats (32). Taken together, these findings suggest a specific role for FGF-2 during wound healing that, despite the apparent redundancy of FGF signaling, cannot be covered for by other FGF family members.
3. TGF-P Superfamily Members and Downstream Signaling Molecules
The TGF-P superfamily encompasses a diverse range of proteins, many of which play important roles during development and differentiation. Mammalian members include TGF-P1-3, bone morphogenetic proteins (BMPs), Mullerian inhibiting substance, inhibins, and activins (reviewed in ref. 33). Their biological effects are mediated by heteromeric receptor complexes, which signal via activation of intracellular Smad signaling pathways (reviewed in ref. 34). TGF-P is one of the most studied molecules in the wound-healing scenario. This growth and differentiation factor is found in large amounts in platelets and is also produced by several cell types that are present in a wound, including activated macrophages, fibroblasts, and keratinocytes (35). Three TGF-P isoforms (TGF-P 1, TGF-P2, and TGF-P3) are present in mammals and have both distinct and overlapping functions. In vitro, these molecules have been shown to be mitogenic for fibroblasts, but they inhibit proliferation of most other cells. Furthermore, TGF-Ps modulate differentiation processes and are very potent stimulators of the expression of extracellular matrix (ECM) proteins and integrins (33). Therefore, they have the properties expected of wound cytokines. Indeed, a series of studies has demonstrated a beneficial effect of exogenous TGF-P for wound repair (35). Furthermore, endogenous TGF-P is likely to play an important role in wound healing, since all three types of mammalian TGF-P are expressed during repair, with each isoform having a characteristic distribution in the wound tissue (36,37). TGF-P induction is modulated in a complicated manner by systemic glucocorticoid treatment of wild-type mice, suggesting that aberrant expression of TGF-P 1, TGF-P2, and TGF-P3 is associated with the wound-healing defect seen in these mice (37). Additionally, TGF-P is particularly important for the scarring response; it has been shown that TGF-P 1 and TGF-P2 induce cutaneous scarring, whereas TGF-P3 seems to inhibit this effect (38,39).
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