How important is collagen destruction in arthritis? A study with collagenase-resistant knockin mice

Aggecan和胶原蛋白是软骨中重要的结构分子。它们一起允许软骨承受重量并抵抗压缩。在关节炎中，胶原蛋白被胶原酶降解，而聚集蛋白聚糖被聚集蛋白聚糖酶降解。聚集蛋白聚糖损失是软骨疾病的特征。早期聚集蛋白聚糖的损失是有据可查的，通常先于临床症状，这表明它是软骨病理学的起始步骤。在外植体培养中，聚集蛋白聚糖损失先于胶原损伤，然而，尚不清楚抑制聚集蛋白聚糖酶是否足以长期阻断软骨损伤。相反，其他研究表明聚集蛋白聚糖仅在胶原支架受损后丢失。这些研究表明，胶原支架的剪切可能会引发聚集蛋白聚糖释放;随着进行性变性和胶原剪切，更多的聚集蛋白聚糖丢失，直到最终支架严重受损，聚集蛋白聚糖严重耗尽。软骨只能承受有限程度的胶原蛋白降解，并且对网络的任何重大损害被广泛认为是不可修复的。目前还不清楚聚集蛋白聚糖酶和胶原酶在引发和维持软骨损伤中的作用。我们有聚集蛋白聚糖对聚集蛋白聚糖酶耐药的小鼠和聚集蛋白聚糖酶失活的小鼠。我们还将培育出具有抗胶原酶胶原蛋白的小鼠。我们将使用这些小鼠来确定胶原酶和聚集蛋白聚糖酶在三种关节疾病模型中对软骨损伤的起始和进展的贡献。我们将确定疾病发作时间、疾病进展速度和疾病严重程度的差异。结果将显示是否一个或两个活动是重要的关节疾病的开始和进展。这将揭示是否需要单一或联合治疗关节炎的管理。这项研究将为制药业提供有关预防关节疾病新药开发方向的信息。

Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.