Type 2 diabetes significantly increases the risk and severity of periodontal disease. In humans two different models have been proposed for periodontal disease, a chronic continuous model and a random burst model. Current evidence does not rule out one or the other. We will use a ligature induced model of periodontal bone loss in the rat that exhibits features consistent with the random burst model. The ligature facilitates bacterial invasion of connective tissue leading to an increase in cytokine expression, loss of connective tissue attachment, inflammatory cell recruitment close to bone and alveolar bone resorption. Preliminary data indicate that diabetes significantly alters the progression of periodontal destruction in the rat ligature model in a way that is consistent with the known impact of diabetes on the human periodontium. When ligatures are removed there is a period of bone formation associated with osseous coupling that is significantly reduced in type 2 Zucker diabetic fatty rats compared to genetically matched normoglycemic lean controls. A significant advantage of this model is that the period of bone resorption and formation are both known and can be quantified separately. Thus, the two critical variables needed for the studies below can be accurately assessed. In order to maintain bone mass coupling ensures that bone formation follows resorption. It is possible that diabetes enhances alveolar bone loss by suppression of coupling due to diabetes-impaired bone formation. Thus, we will focus on a previously unreported aspect, that diabetes interferes with the formation of new alveolar bone following an episode of bone resorption. The goal of the proposed studies is to investigate a hypothesis that diabetes through enhanced production of TNF-D increases apoptosis and thereby interferes with coupling of alveolar bone resorption and formation. Aim 1 will investigate whether uncoupling in the periodontium of diabetic animals is due to enhanced levels of TNF-D. These studies will use a TNF-specific inhibitor, etanercept applied by i.p. injection to study the role of TNF-Q Aim 2 will determine whether diabetes enhanced apoptosis represents a functionally significant mechanism for uncoupling of bone formation and resorption in the periodontium. These studies will use i.p. injection of a caspase inhibitor to block apoptosis during bone formation following an episode of periodontal bone resorption in the rat ligature model. Aim 3 will study whether TNF plays a critical role in diabetes enhanced fibroblast apoptosis, diabetes altered gene expression determined by mRNA profiling and matrix metalloproteinase activity. These studies will use the rat model and TNF blocker described in Aim 1. [unreadable] [unreadable] [unreadable]