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Development of a new therapeutic approach for senile osteoporosis using bone matrix deoorin

利用骨基质脱氧蛋白开发老年骨质疏松症新治疗方法

基本信息

批准号：
06557055
负责人：
MATSUMOTO Toshio
金额：
$ 5.7万
依托单位：
University of Tokyo School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Bone matrix decorin binds transforming growth factor (TGF)-beta with high affinity, and the binding of TGF-beta with decorin increases its binding to TGF-beta receptors (Takeuchi et al. J Biol Chem 269 : 32634,1994). These results suggested that decorin may serve as a binding protein of TGF-beta in bone matrix, and may modilate the actions of TGF-beta during bone formation process. It has been postulated that a reduction in the actions of growth factors including TGF-beta plays an important role in the development of senile osteoporosis. The present studies are undertaken to clarify the role of decorin in the deposition of TGF-beta into bone matrix as well as the regulation of TGF-beta actions in bone. Furthermore, recombinant decorin was prepared in order to develop a new therapeutic approach to senile osteoporosis by a targeted application of recombinant decorin to bone.Osteoblasts posess specific binding sites for decorin on the plasma membrane, and the binding of decorin to its binding sites causes an internalization and degradation of decorin. Binding of TGF-beta-bound decorin to its binding sites facilitates the binding of TGF-beta to TGF-beta receptors, which appears to be the mechanism whereby the binding of TGF-beta to decorin enhances its actions. The present studies also demonstrated that binding sites for decorin is upregulated by active vitamin D metabolites. Although age-related changes in the content of decroin in bovine bone matrix was examined, no obvious changes could be detected. Finally, recombinant human decorin was prepared by transfecting human decorine c DNA into CHO cells. However, enough materials could not be obtained to allow investigations into the in vivo effect of recombinant decorin in the prevention of age-related bone loss.

骨基质核心蛋白聚糖以高亲和力结合转化生长因子（TGF）-β，TGF-β与核心蛋白聚糖的结合增加了其与TGF-β受体的结合（Takeuchi等，J Biol Chem 269：32634，1994）。提示核心蛋白聚糖可能是骨基质中TGF-β的结合蛋白，在骨形成过程中调节TGF-β的作用。据推测，包括TGF-β在内的生长因子作用的减少在老年性骨质疏松症的发展中起重要作用。本研究旨在阐明核心蛋白聚糖在TGF-β沉积到骨基质中的作用以及TGF-β在骨中的调节作用。此外，我们还制备了重组核心蛋白聚糖，目的是将重组核心蛋白聚糖靶向应用于骨组织，为老年性骨质疏松症的治疗提供新的途径，成骨细胞膜上具有核心蛋白聚糖的特异性结合位点，核心蛋白聚糖与其结合位点的结合导致核心蛋白聚糖的内化和降解。TGF-β结合的核心蛋白聚糖与其结合位点的结合促进TGF-β与TGF-β受体的结合，这似乎是TGF-β与核心蛋白聚糖的结合增强其作用的机制。目前的研究还表明，核心蛋白聚糖的结合位点被活性维生素D代谢物上调。虽然检查了牛骨基质中去铬蛋白含量的年龄相关变化，但未检测到明显变化。最后，将人核心蛋白聚糖c DNA转染CHO细胞，制备重组人核心蛋白聚糖。然而，无法获得足够的材料来研究重组核心蛋白聚糖在预防年龄相关性骨丢失中的体内作用。