COLLAGENASE REMOVAL IN OSTEOARTHRITIS

描述(摘自申请)：胶原酶-3在 骨关节炎的病理生理学正在变得非常成熟。这种酶 高水平裂解软骨的主要蛋白质成分--II型胶原 专一性。多项研究已证实胶原酶-3水平升高 (和其他基质金属蛋白酶)在关节炎滑液中的表达。我们有 显示成骨细胞、软骨细胞和成纤维细胞可以清除胶原酶-3 通过将酶与特定的受体结合，从周围环境中分离出来。这个 然后，酶通过内吞作用内化和降解。 受体，低密度脂蛋白受体相关蛋白(LRP)。这样的一个 过程提供了一种机制，用于受控消除潜在的 破坏性酶。此外，我们已经证明了骨关节炎 或许，软骨细胞移除这种酶的能力较弱。 加剧了关节间隙中胶原酶-3的产生。在……里面 此外，我们还发现他汀类药物可以促进胶原酶-3的清除。 由骨关节炎软骨细胞引起。因此，我们的假设是增强 骨性关节炎软骨细胞LRP丰度的研究 他汀类药物提供了一种受控清除胶原酶-3的机制 软骨的细胞外空间，在正常生理条件下具有功能。 因此，本提案的目的是进一步说明这一进程的特点，并 他汀类药物的作用部位。这将通过以下方式实现：i) 软骨细胞中胶原酶去除过程的特征。Ii) 胶原酶清除下调的原因探讨 系统在骨关节炎软骨细胞中的表达。三)检查他汀类药物的效果 骨性关节炎软骨细胞胶原酶去除过程的研究。四) 他汀类药物清除胶原酶作用机理的研究 进程。这项工作将为深入了解糖尿病的基本病理生理学提供帮助。 骨关节炎，将成为新的治疗方案的基础，以及 确定这种治疗的机制。

DESCRIPTION (Taken from the application): The role of collagenase-3 in the pathophysiology of osteoarthritis is becoming well-established. This enzyme cleaves collagen II (the major protein component of cartilage) with high specificity. Several studies have identified increased levels of collagenase-3 (and other matrix metalloproteinases) in arthritic synovial fluid. We have shown that osteoblasts, chondrocytes and fibroblasts can remove collagenase-3 from the surrounding milieu by binding the enzyme to a specific receptor. The enzyme is then internalized and degraded through the actions of the endocytotic receptor, the low-density lipoprotein-receptor related-protein (LRP). Such a process provides a mechanism for the controlled elimination of a potentially destructive enzyme. Further, we have demonstrated that osteoarthritic chondrocytes appear to have lesser abilities to remove this enzyme, perhaps exacerbating their production of collagenase-3 in the joint spaces. In addition, we have shown that statins can enhance the removal of collagenase-3 by osteoarthritic chondrocytes. As a result, our hypothesis is that enhancement of abundance of the LRP by treatment of osteoarthritic chondrocytes with statins provides a mechanism for controlled removal of collagenase-3 from the extracellular space of cartilage, which is functional under normal physiology. Thus, the aims of this proposal are to further characterize this process and the site of action of the statins. This will be accomplished by: i) characterizing the collagenase removal process in chondrocytes. ii) investigating the cause of the down-regulation of the collagenase removal system in osteoarthritic chondrocytes. iii) examining the effect of the statins on the collagenase removal process in osteoarthritic chondrocytes. iv) determining the mechanism of action of the statins on the collagenase removal process. This work will offer insight into the basic pathophysiology of osteoarthritis and will be the basis for a new treatment option as well as determining the mechanisms of that treatment.