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变得非常成熟。这种酶 切割胶原蛋白II（软骨的主要蛋白质成分）， 的特异性几项研究已经确定了胶原酶-3水平的增加 (and其它基质金属蛋白酶）。我们有 显示成骨细胞、软骨细胞和成纤维细胞可以去除胶原酶-3， 通过将酶与特定的受体结合而从周围环境中分离出来。的 然后，酶通过内吞作用被内化和降解， 低密度脂蛋白受体相关蛋白（LRP）。这样的 过程提供了一种机制，用于控制消除潜在的 破坏酶此外，我们已经证明， 软骨细胞似乎有较低的能力，以消除这种酶，也许 加剧了它们在关节间隙中胶原酶-3的产生。在 此外，我们已经证明他汀类药物可以增强胶原酶-3的清除， 由骨关节炎的软骨细胞引起。因此，我们的假设是， 通过用以下物质处理骨关节炎软骨细胞， 他汀类药物提供了一种机制，用于控制胶原酶-3从 软骨的细胞外空间，其在正常生理学下具有功能。 因此，本提案的目的是进一步说明这一进程的特点， 他汀类药物的作用部位这将通过以下方式实现：i） 表征软骨细胞中的胶原酶去除过程。ii）第二阶段 探讨胶原酶清除下调的原因 系统中的骨关节炎软骨细胞。iii）检查他汀类药物的作用 对骨关节炎软骨细胞中胶原酶去除过程的影响。iv） 确定他汀类药物对胶原酶去除的作用机制 过程这项工作将提供深入了解的基本病理生理学， 骨关节炎，并将成为新的治疗选择的基础， 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.