Mechanisms involved in cartilage proteoglycan catabolism
Mechanisms involved in cartilage proteoglycan catabolism
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DOI：
10.1016/s0945-053x(00)00078-0
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发表时间：
2000-08-01
期刊：
影响因子：
6.9
通讯作者：
Little, CB
中科院分区：
文献类型：
--
作者：
Caterson, B;Flannery, CR;Little, CB
软骨蛋白多糖聚集蛋白的分解代谢增加是导致关节炎关节疾病中关节软骨变性的主要病理过程。因此，作为聚集蛋白分子固有成分的磺化糖胺聚糖的损失会损害软骨基质的功能和结构完整性，并最终导致组织无法抵抗关节接合过程中施加的压缩载荷。随着时间的推移，这个过程会导致不可逆的软骨侵蚀。聚集蛋白的原位降解是一种蛋白质水解过程，涉及位于核心蛋白内的特定肽键的裂解。在这一过程中，最具特征的酶活性是由锌依赖性金属蛋白酶产生的。基质金属蛋白酶（MMPs）的体外聚合酶解已被广泛研究；然而，现在人们已经认识到，在关节软骨中负责聚集蛋白原位降解的主要蛋白酶是聚集酶，最近发现的两种亚型是“带血栓反应蛋白基元的A崩解素和金属蛋白酶”（ADAMTS）基因家族的成员。在这篇综述中，我们描述了：(i)单克隆抗体技术的发展，以识别聚合蛋白降解产物上的分解代谢新表位；（ii）在研究中使用这些新表位抗体来描述和鉴定负责软骨聚集蛋白代谢的酶；（iii）可溶性软骨聚集酶的生化特性及其在原位的差异表达；（四）研究软骨聚集蛋白分解代谢的模型培养系统。这些研究清楚地表明，在关节炎关节疾病的早期阶段，在明显的胶原分解代谢和组织完整性破坏之前，“聚合酶”主要负责关节软骨的分解代谢和聚集蛋白的损失。在后期，当胶原分解代谢发生时，有证据表明mmp介导的组织中剩余的一小部分聚集蛋白降解，但这与持续的聚集酶活性无关。此外，当明显的胶原降解时，MMPs也会启动连接蛋白的分解代谢。(C) 2000 Elsevier Science B.V./国际基质生物学学会。版权所有。
The increased catabolism of the cartilage proteoglycan aggrecan is a principal pathological process which leads to the degeneration of articular cartilage in arthritic joint diseases. The consequent loss of sulphated glycosaminoglycans, which are intrinsic components of the aggrecan molecule, compromises both the functional and structural integrity of the cartilage matrix and ultimately renders the tissue incapable of resisting the compressive loads applied during joint articulation. Over time, this process leads to irreversible cartilage erosion. In situ degradation of aggrecan is a proteolytic process involving cleavage at specific peptide bonds located within the core protein. The most well characterised enzymatic activities contributing to this process are engendered by zinc-dependent metalloproteinases. In vitro aggrecanolysis by matrix metalloproteinases (MMPs) has been widely studied; however, it is now well recognised that the principal proteinases responsible for aggrecan degradation in situ in articular cartilage are the aggrecanases, two recently identified isoforms of which are members of the 'A Disintegrin And Metalloproteinase with Thrombospondin motifs' (ADAMTS) gene family. In this review we have described: (i) the development of monoclonal antibody technologies to identify catabolic neoepitopes on aggrecan degradation products; (ii) the use of such neoepitope antibodies in studies designed to characterise and identify the enzymes responsible for cartilage aggrecan metabolism; (iii) the biochemical properties of soluble cartilage aggrecanase(s) and their differential expression in situ; and (iv) model culture systems for studying cartilage aggrecan catabolism. These studies have clearly established that 'aggrecanase(s)' is primarily responsible for the catabolism and loss of aggrecan from articular cartilage in the early stages of arthritic joint diseases that precede overt collagen catabolism and disruption of the tissue integrity. At later stages, when collagen catabolism is occurring, there is evidence for MMP-mediated degradation of the small proportion of aggrecan remaining in the tissue, but this occurs independently of continued aggrecanase activity. Furthermore, the catabolism of link proteins by MMPs is also initiated when overt collagen degradation is evident. (C) 2000 Elsevier Science B.V./International Society of Matrix Biology. All rights reserved.