Growth Factor Regulation of Fracture Repair

Abstract

Fracture repair can be considered as a biologically optimal process resulting in the restoration of injured skeletal tissue to a state of normal structure and function. Although the process leads to healing in the vast majority of cases, a small but significant proportion of fractures result in delayed union or persistent nonunion. Surgical interventions have been directed toward enhancing the fracture repair process, normalizing the rate of healing, and decreasing the likelihood of nonunion. During fracture repair, a number of growth factors, cytokines, and their cognate receptors are present at elevated levels in and around the fracture site. Many of these proteins are normally expressed in skeletal tissue, and others are released from associated inflammatory cells at the site of injury. The induction of these proteins is regulated both spatially and temporally, suggesting that they play an active role in promoting fracture repair. The following review will summarize the current literature on the roles of the major cytokines and growth factors involved in fracture repair. In addition, the signaling cascades induced by these molecules will be discussed. While many cytokine and growth factor signaling events have not been specifically examined in the context of fracture repair, a large body of literature on signal transduction has emanated from studies on these molecules in embryonic bone development. Given the conserved nature of these molecules and their signaling cascades from Drosophila to humans, and the similarities between the fracture repair process and embryonic bone development, it seems highly probable that these downstream signaling events are conserved in fracture repair. Fracture repair can be envisioned as involving five distinguishable processes, including the immediate response to injury, intramembranous bone formation, chondrogenesis, endochondral bone formation leading to the reestablishment of load bearing function, and bone remodeling. While these processes may be discussed individually, it should be recognized that the first four occur simultaneously during fracture repair and are likely to influence one another. Extensive remodeling of the newly formed bone follows these four concurrent processes and facilitates the reestablishment of the full biomechanical integrity of the bone. A number of investigators have commented on the similarities between the repair process and embryonic bone formation and indeed a number of specific events characteristic of embryonic bone formation are reiterated in fracture repair. This is especially evident as one begins to examine the specifics of local factors regulating fracture repair, specifically those involved in the events of endochondral bone formation. The immediate response to injury from the fracture trauma is the initiating event of the fracture repair process. Fracture trauma involves not only an interruption of skeletal integrity but also a disruption of the normal vascular structures and nutrient flow at the fracture site. This leads to reduce oxygen tension, disruption of the marrow architecture, and results in the infiltration of inflammatory cells, macrophages, and degranulating platelets during formation of a hematoma.1, 2 While it is likely that the mechanical stresses, changes in oxygen tension, and loss of vascular nutrients at the fracture site may signal some aspects of the healing process, the dominant initiators of fracture repair are most likely the numerous cytokines and growth factors released into the fracture site.3 To date the majority of research on fracture repair has focused on the actions of a relatively limited number of cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha, and macrophage colony-stimulating factor as well as the local growth factors fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and the bone morphogenetic proteins (BMPs)-2, -3, -4, and -7. It is interesting to note that the majority of the factors mentioned have well described roles in the formation and patterning of the embryonic skeleton or in the homeostatic maintenance of the mature skeleton. During the immediate injury response, the first detectable factors include PDGF and TGF-β released by the degranulating platelets.3 This is closely followed by infiltrating macrophages and other inflammatory cells that secrete FGF and additional PDGF and TGF-β. Presumably, these inflammatory cells also release a variety of cytokines including IL-1 and IL-6; however, this has only been demonstrated indirectly and no comprehensive data are available on the spatiotemporal profile of the proinflammatory and immune cytokine expression during the fracture repair process.4 Thus within the first hours post fracture, a complex milieu of factors involved in bone repair can be detected in the fracture site. Some or all of these factors are presumably the initiators of