ENDOSTEAL BONE VOLUME REGULATION AND OSTEOPOROSIS

研究骨体积调节对我们的长期发展至关重要 目的是治疗和预防骨质疏松症。 骨体积为 通过骨形成和骨吸收的速率确定， 包括我们在内的几个实验室最近的研究表明， 生长因子可通过以下方式局部调节骨形成 刺激成骨细胞增殖和活性。 本 最后，我们已经纯化到明显的同质性，骨细胞生长 来自人骨基质的称为Skeletal生长因子（SGF）的因子 我们对人SGF结构的研究表明， 与人IGF-II同源。 我们发现了多种生长因子 包括人的SGF/IGF-II、IGF-I、TGF-β、PDGF和碱性FGF 骨基质和人骨细胞条件培养基中。基于 在过去的研究中，我们和其他人提出了这样一个概念， 生长因子的产生在调节 骨代谢 该项目的主要重点将是 探讨SGF/IGF-1合成和分泌的调控。 II及其结合蛋白。 对此，我们将测试3 相关假设：1）SGF/IGF-II的合成受到调节， 几个不同的步骤，即，8个控制点 （范围从转录到ECF byu结合蛋白的结合） 每一个都将被研究。 另外我们 将从骨细胞条件化中纯化SGF、IGF-II结合蛋白 培养基和人骨基质，并确定 结合蛋白对SGF/IGF-II诱导的细胞增殖和 矩阵X合成2)生长因子的调节剂 不同生长因子的合成是不同的。 即将 IGF-II包括IGF-I、TGFB和碱性FGF。 我们将 还确定SGF/IGF-II和胶原蛋白的合成是否 共同调节或独立调节，3）SGF和其他 由骨细胞分泌的生长因子被分配到 两个隔室，a）骨基质（在此 隔室可以在释放后的稍后时间起作用， 破骨细胞）和B）ECF（在该室中的生长因子可以 AVT急性调节增殖和成熟细胞功能 的成骨细胞），我们将通过测试来评估这种假设。 不同的影响因素。 拟议的研究将 使用体外实验模型系统（骨 培养的细胞和vone器官），SGF/IGF-II特异性抗体， SGF/IGF-II cDNA证明，放射性标记的SGF和验证的生长 因子分析 预计这些研究将提供 在局部水平上骨形成的有价值的信息。

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.