ENDOSTEAL BONE VOLUME REGULATION AND OSTEOPOROSIS

骨量调节的研究对我们的长远发展是至关重要的 目标是治愈和预防骨质疏松症。骨体积是 由骨形成和骨吸收的速率和 包括我们在内的几个实验室最近的研究表明 生长因子可能通过以下方式在局部调节骨形成 刺激成骨细胞的增殖和活性。对这件事 最后我们纯化到明显的同质性，一种骨细胞的生长 人骨基质中的骨生长因子(SGF) 以及我们对人SGF揭示序列结构的研究 与人IGF-II同源。我们发现了多种增长因素 包括SGF/IGF-II、IGF-I、转化生长因子-B、PDGF和碱性成纤维细胞生长因子 骨基质和人骨细胞条件培养液。基于 在过去的研究中，我们和其他人提出了本地的概念 生长因子的产生在调控中起着关键作用。 骨骼新陈代谢。该项目的主要重点将是 探讨SGF/IGF-2合成和分泌的调节 II及其结合蛋白。在这方面，我们将测试3 相关假说：1)SGF/IGF-II的合成在 几个不同的步骤，即适度的8个控制点 (ECF BYU结合蛋白从转录到结合) 将对其中的每一个进行研究。此外，我们 将从有条件的骨髓细胞中纯化SGF.IGF-II结合蛋白 培养液和人骨基质，并测定其效果 SGF/IGF-II结合蛋白诱导的细胞增殖和 矩阵x综合。2)生长因子的调节剂 不同生长因子的合成不同。那些即将成为 与SGF比较，IGF-II包括IGF-I、TGFb和碱性成纤维细胞生长因子。我们会 还要确定SGF/IGF-II和胶原的合成是否 共同监管或独立监管，3)SGF和其他 骨细胞分泌的生长因子被分成 两个隔室，a)骨基质(此中的生长因子 隔间可以在释放后的稍后时间通过 破骨细胞)和b)ECF(该隔室中的生长因子可以 AVT敏锐地调节细胞的增殖和成熟功能 成骨细胞)，我们将通过测试来评估这种假设 此分区上的各种效应器。拟议研究将 使用体外实验模型系统(骨)进行BE 培养中的细胞和VONE器官)，SGF/IGF-II特异性抗体， SGF/IGF-II的cDNA验证、放射修饰的SGF及其生长验证 因子分析。预计这些研究将提供 关于当地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.