MECHANISMS OF GLUCOCORTICOID-GROWTH FACTOR INTERACTIONS

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Next to prevention, limiting disease progression and inducing regeneration of lost tissues are the two most important goals of modern periodontal therapy. This proposal, in two parts, deals with these two problems. The first part intends to explore the mechanisms of action of glucocorticoid induced synergy of platelet-derived growth factor (PDGF) mitogenesis in vitro. A therapeutic combination comprised of PDGF and dexamethasone complexed in an insoluble collage matrix is capable of inducing regeneration of the periodontium. It is likely that in vivo PDGF/Dex provides an initial molecular signal inducing capable cells to proliferate, migrate and subsequently initiate a complex cascade of events which ultimately results in tissue regeneration. The mechanism for the synergistic effect of Dex on PDGF mitogenesis is not clear. Therefore this proposal will explore the biochemical and molecular basis for the synergistic effect of dexamethasone on PDGF mitogenesis, in vitro. Utilizing strains of diploid human gingival and periodontal ligament fibroblasts, the proposed experiments will determine if Dex affects the cycling fraction of cells or the rate of transit through the cell cycle. Experiments to determine possible biochemical mechanisms by which hormones and growth factors may interact to regulate the fraction of cells proliferating and/or the rate at which the cycling fraction proliferates are planned. The molecular basis of the operative biochemical pathway(s) will be explored using the modern techniques of molecular biology. The second part intends to study the effects of tetracyclines on connective tissue degradation in vivo, using a ligature induced model of periodontitis in non-human primates. Tetracyclines have long been used as adjuncts for the treatment of periodontal disease because of their antimicrobial effects, their unique ability to non-antimicrobial properties that are also therapeutically advantageous. These include the tetracycline ability to directly inhibit host collagenolytic enzymes thereby inhibiting connective tissue degradation, including bone resorption, that characterizes a variety of disease processes including periodontal disease. The long-term goal of this research is to demonstrate that tetracyclines, including the chemically modified tetracycline, devoid of antimicrobial properties, can prevent or impede periodontal breakdown. The effects of systemically administered tetracyclines on the progression of ligature induced periodontitis will be monitored using both clinical and biochemical parameters in monkeys inoculated with Porphyromonas gingivalis.