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

骨基质核心蛋白以高亲和力结合转化生长因子-β，并且转化生长因子-β与核心蛋白的结合增加了其与转化生长因子-β受体的结合(Takeuchi et al.生物化学269：32634,1994)。提示核心蛋白聚糖可能是骨基质中转化生长因子-β的结合蛋白，并可能调节转化生长因子-β在骨形成过程中的作用。据推测，包括转化生长因子-β在内的生长因子作用的减少在老年性骨质疏松症的发生发展中起着重要作用。本研究旨在阐明核心蛋白聚糖在转化生长因子-β沉积到骨基质中的作用以及转化生长因子-β在骨中的作用。此外，为了开发一种新的治疗老年性骨质疏松症的方法，制备了重组核心蛋白聚糖，成骨细胞在质膜上具有核心蛋白聚糖的特异结合位点，核心蛋白聚糖与其结合部位的结合导致核心蛋白核心蛋白的内化和降解。结合结合素的结合部位促进了转化生长因子-β与转化生长因子-β受体的结合，这似乎是转化生长因子-β与结合素结合增强其作用的机制。目前的研究还表明，核心蛋白结合素的结合部位被活性维生素D代谢产物上调。虽然观察了牛骨基质中蜕皮素含量的增龄变化，但未检测到明显的变化。最后，将人Decorine c DNA导入CHO细胞，制备重组人Decorin。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方面的体内效应。

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.