This project is based on the concept that interactions between local and systemic factors are important in the regulation of bone metabolism and that studies of these interactions will provide insight not only into physiologic regulation of the skeleton, but also into pathologic mechanisms and therapeutic approaches in metabolic bone disease, particularly osteoporosis. The studies proposed will use organ cultures of fetal and neonatal bone and cell cultures of the osteoblast phenotype, from both immortalized and transformed cell lines, to examine the complex hormonal regulation of skeletal tissues. Our major hypothesis is that endogenous prostaglandins are central to the ability of the skeleton to respond to local perturbations and that the role of prostaglandins is continuously modified by systemic hormones. The specific avenues to be explored include studies on the mechanisms of the effects of prostaglandins and related eicosanoids on bone resorption and formation, analysis of the regulation of endogenous prostaglandin production in bone, studies on interactions between prostaglandins, cytokines or growth factors and systemic hormones such as parathyroid hormone and 1,25 dihydroxyvitamin D. In addition, we will attempt to develop a reliable in vitro model to study the mechanism of the anabolic effect of PTH. An organ culture model which shows orderly bone growth with mineralization will be used to determine whether mineralization is regulated. We will attempt to find markers for bone resorption using in vitro models, which can then be used to assess resorption in vivo.