Cartilage destruction in arthritis: Mechanism of aggrecanase and matrix metalloproteinase action in vivo and in vitro

关节炎是一种导致疼痛、畸形和残疾的疾病。关节炎缺乏足够的治疗方法，部分反映了我们对疾病进展和软骨破坏所涉及的生化事件的理解有限。软骨中存在两种不同的酶家族。这些是MMP和ADAMTS家族。这些酶家族对于正常生长和骨骼发育中的软骨周转是重要的。然而，不受调节的酶活性导致软骨加速分解，导致被认为是关节炎的病理。虽然已经在实验室中研究了MMP和ADAMTS家族的一些活性，但还没有体内研究来确定哪个家族负责软骨破坏，因此哪个家族最适合用于药物靶向。该项目将创建转基因小鼠，对MMP或ADAMTS酶具有抗性。这些小鼠将用于实验性关节炎模型，以确定哪些酶在引发疾病中起主要作用，哪些酶参与疾病进展，哪些酶可能对修复很重要。在平行研究中，将研究高度专业化的基质分子硫酸角质素在软骨破坏中的作用。有初步证据表明，硫酸角质素可能参与ADAMTS活性的调节。将研究硫酸角质素作用的可能的直接和间接方式。该关节炎项目的结果将（a）产生关于疾病作用机制的新信息;（B）确定合理设计疾病缓解药物的靶点;（c）阐明正常骨骼生长和软骨修复所涉及的生化过程;以及（d）提供用于测试关节炎疗法功效的新的体内模型。

Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the pathology recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied in the laboratory, there have been no in vivo studies to determine which family is responsible for cartilage destruction, and which is therefore most appropriate for targeting by drugs. This project will create genetically-modified mice, resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental arthritis models to determine which enzymes play the major role in initiating disease, which enzymes are involved in disease progression and which enzymes may be important for repair. In parallel studies, the highly specialised matrix molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is preliminary evidence to suggest that keratan sulphate may be involved in the regulation of ADAMTS activity. The possible direct and indirect modalities of keratan sulphate action will be investigated. The results of this arthritis project will (a) yield new information on the mechanism of disease action; (b) identify targets for the rational design of disease-modifying drugs; (c) elucidate biochemical processes involved in normal skeletal growth and cartilage repair; and (d) provide new in vivo models for testing the efficacy of arthritis therapies.