Congenital skeletal anomalies such as infantile malignant osteopetrosis and craniometaphyseal dysplasia potentially arise from genetic bone lesions or epigenetic events. Bone forming osteoblasts, bone resorbing osteoclasts, and/or their precursor cells may be affected. Craniofacial reconstruction is dependent on host graft interaction to induce new bone formation. The composition of the bone graft is important to elicit net bone deposition as opposed to net bone resorption. Relatively little is known about the complex genetic and epigenetic factors that regular bone development and remodelling. The proposed studies are intended to provide detailed information about the interactions between bone cells, bone cell precursor populations, and extracellular matrices. Local and systemic signals apparently interface with the genetic program to orchestrate precise bone modeling. The cellular basis of this interaction is unknown. Isolated osteoclasts and monocyte derived multinucleated giant cells will be exploited to investigate osteoclast differentiation and function in vitro. In addition an osteoblast differentiation system will be used to investigate osteoblast-osteoclast interactions in vitro. Osteoclast differentiation will be monitored by localizing and quantitating the emergence of osteoclast specific proteins employing osteoclast specific monoclonal antibodies. We will further determine if osteoclast products in turn effect osteoclast differentiation or expression. We will accomplish this by identifying cellular and matrix factors responsible for osteoclast and osteoblast interactions. It is our aim to determine if local matrix, diffusable cell products, or cell contact are required for skeletal remodelling. Such studies will also contribute to our understanding of normal and inflammatory bone loss and aid in devising therapies for periodontal disease and diabetes associated osteopenia.