The long-term goal of these studies is to understand the cellular and molecular mechanisms that control bone development and homeostasis. During the past funding period, significant progress has been made in identifying the multiple roles of vascular endothelial growth factor (VEGF) in skeletal development. These roles include serving as chemotactic factor for vascular invasion into cartilage models of future bones, serving as survival factor for chondrocytes in hypoxic regions, promoting matrix production by osteoblasts and chondrocytes and stimulating osteoclast formation and migration. Through the use of conditional targeting techniques for cell-specific inactivation of VEGF and VEGF receptor genes in mice (Aims 1 and 2), the work proposed is aimed at identifying the cellular mechanisms by which VEGF exerts its skeletal functions. Experiments using inducible, conditional targeting strategies to inactivate both VEGF and VEGF receptors are also planned to find out whether VEGF is required for postnatal skeletal growth and homeostasis. In studies of a mouse model for cherubism, a genetic disorder in humans, the investigators seek to identify mechanisms in myeloid cells that are important for regulation of macrophage/osteoclast differentiation. Based on extensive studies of mice in which the most common mutation in cherubism families has been knocked into the mouse gene, the investigators believe that cherubism is a hematopoietic disorder and that mutant myeloid progenitor cells are hyper-responsive to cytokines that stimulate differentiation to macrophages and osteoclasts. Through a combination of in vitro and in vivo studies (Aim 3) the signaling pathways that are affected by the cherubism mutations will be identified. Bone marrow cells from control and cherubism mutant mice will be compared in cell signaling studies of osteoclast formation in vitro. In vivo studies of the mutant mice will test the hypothesis that the mutations in cherubism cause a combination of molecular gain-of-function and loss-of-function effects. The outcomes of the proposed work will provide insights into cellular mechanisms of bone formation and resorption that are altered in skeletal disorders of excess bone formation and inflammatory bone loss.
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