The precise mechanism whereby osteoblasts mediate osteoclastic bone resorption is unclear. One widely-held hypothesis is that activated osteoblasts secrete cytokines that directly or indirectly influence osteoclast formation or function. Although the nature of these putative cytokines is unknown, compelling in vivo and in vitro data have emerged to support a role for colony-stimulating factor-1 (CSF-1) as an osteoblast-derived factor involved in osteoclast formation. Thus, in vivo, deficiency of CSF-1 in the op/op osteopetrotic mouse causes a failure of osteoclast formation and bone resorption while in vitro studies have demonstrated that CSF-1 is critical for the proliferation and differentiation of osteoclast progenitors, that CSF-1 stimulates bone resorption in the fetal mouse metacarpal assay, and that CSF-1 receptors are present on osteoclasts. CSF-1 is synthesized as a soluble or cell surface protein, and while we know that osteoblasts synthesize both forms of CSF-1 I constitutively and in response to osteotropic agents, little is known of their physiologic significance in bone remodeling. Additionally, while we know that two key osteotropic agents, parathyroid hormone (PTH) and tumor necrosis factor (TNF) increase expression of the CSF-1 gene in osteoblasts, the precise mechanism by which they do so is unclear. Finally, the precise physiologic role of CSF-1 in bone remodeling in vivo is unknown. The long term goals of this proposal are therefore: 1. to define the physiologic roles of the cell- surface and soluble forms of CSF-1 in bone, by examining the effects of cell-surface CSF-1 on osteoclast signaling in vitro, and by generating two lines of genetically-altered mice that are each deficient in one of the CSF-1 I isoforms; 2. to characterize the cellular mechanisms by which TNF and PTH increase CSF-1 transcription in osteoblasts by characterizing the NF-kappaB proteins that mediate TNF-induced CSF-1 gene expression and by identifying and characterizing the CSF-1 promoter elements by which PTH mediates this response; and 3. to analyze the role of CSF-1 in bone remodeling in vivo by characterizing in vivo and in vitro a transgenic mouse model with targeted overexpression of CSF-1 in osteoblasts. These studies will help to elucidate the regulation and role of a cytokine which is critical in osteoclast development, and will improve our understanding of the mechanisms of physiologic bone resorption, and that induced by osteotropic agents.
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