Skeletal tissue response to cytokines.

Communication among individual cell types that populate connective tissues such as cartilage or bone is of critical importance in determining the phenotypic properties of these tissues under both physiologic and pathologic conditions. Cytokines, which may be defined as soluble products released from one cell that can modulate the activity of other cells, play a critical role in this process of cell communication. The introduction of molecular biologic techniques has permitted identification of specific cytokines previously characterized on the basis of biologic activities. Cloning and sequencing of these products have provided formal evidence for their existence and allowed identification of the full spectrum of their biologic activities. These results have established that individual cytokines may have multiple biologic activities and that multiple cytokines share common functional properties. Based on these results, the term "cytokine" has been used more generally to include products originally described as growth or differentiation factors, e.g., interleukins, monokines, or lymphokines. Cytokines have an important role in the initiation and control of skeletal tissue growth and development and in regulating bone remodeling in the adult organism. As in other connective tissues, these effects are mediated via paracrine, autocrine, and endocrine mechanisms. In skeletal tissues, cytokines may modulate the activity of resident cells by an additional mechanism. Factors produced locally within bone or arriving via the circulation are incorporated into the mineralized bone matrix, and their release during skeletal remodeling could provide the basis for coupling the activity of bone resorbing and forming cells. The principal cytokines that have been shown to affect skeletal tissues include factors previously described as monokines or lymphokines such as interleukin-1 (IL-1), tumor necrosis factors (TNF-alpha and TNF-beta), and interferon-gamma (IFN-gamma); the colony-stimulating factors; and the so-called growth and differentiation factors including transforming growth factors-alpha and -beta (TGF-alpha and TGF-beta), insulinlike growth factor-I (IGF-I), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Although the effects of the individual cytokines are diverse, it is possible to classify individual factors based on their effects on specific aspects of bone formation or resorption. Significant progress has been made recently toward elucidating the mechanisms of action of the cytokines. Binding studies using radiolabeled ligands have characterized the specific cell surface receptors and defined their distribution and properties among skeletal tissue cells. Various so-called signal transduction pathways have been implicated in mediating these effects...