Studies on bone volume regulation are essential to our long term goals, which are to cure and prevent osteoporosis. Bone volume is determined by the rates of bone formation and bone resorption and recent research in several laboratories including ours suggest that growth factors may act locally to modulate bone formation by stimulating both osteoblast proliferation and activity. To this end we have purified to apparent homogeneity, a bone cell growth factor termed Skeletal Growth Factor (SGF) from human bone matrix and our studies on the structure of human SGF revealed sequence homology with human IGF-II. We found multiple growth factors including SGF/IGF-II, IGF-I, TGF-B, PDGF and basic FGF in humans bone matrix and in human bone cell conditioned medium. Based on past studies we and others have proposed the concept that local production of growth factors plays a key role in the regulation of bone metabolism. The primary focus of this project will e to investigate the regulation of synthesis and secretion of SGF/IGF- II and its binding proteins. In this regard, we will test 3 relevant hypotheses: 1) That SGF/IGF-II synthesis is regulated at several different steps, i.e., a modest of 8 control points (ranging from transcription to binding in ECF byu binding protein) is presented, each one of which will be studied. Additionally, we will purify SGF.IGF-II binding proteins from bone cell conditioned medium and from human bone matrix and determine the effects of binding proteins on SGF/IGF-II induced cell proliferation and matrix x synthesis. 2) That regulatory agents for growth factor synthesis are different for different growth factors. Those to be compare with SGF.IGF-II include IGF-I, TGFB and basic FGF. We will also determine if synthesis of SGF/IGF-II and collagen are coregulated or independently regulated, 3) That SGF and other growth factored upon secretion by bonecells are partitioned into two compartments, a)bone matrix (growth factors in this compartment could act at a later time following release by osteoclast) and b) ECF (growth factors in this compartment could avt acutely to regulate the proliferation and mature cell functions of osteoblasts), We will evaluted this hypotesis by testing various effectors on this partitioning. The propose studies will be carries out using in vitro experimental model systems (bone cells and vone organs in culture), SGF/IGF-II specific antibodies, an SGF/IGF-II cDNA prove, radiolavelled SGF and validated growth factors assays. It is anticipated that theses studies will provide valuable information of bone formation at the local level.
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