Mechanisms involved in cartilage proteoglycan catabolism

The increased catabolism of the cartilage proteoglycan aggrecan is a princi pal pathological process which leads to the degeneration of articular carti lage in arthritic joint diseases. The consequent loss of sulphated glycosam inoglycans, which are intrinsic components of the aggrecan molecule, compro mises both the functional and structural integrity of the cartilage matrix and ultimately renders the tissue incapable of resisting the compressive lo ads applied during joint articulation. Over time, this process leads to irr eversible cartilage erosion. In situ degradation of aggrecan is a proteolyt ic 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 vi tro aggrecanolysis by matrix metalloproteinases (MMPs) has been widely stud ied; however, it is now well recognised that the principal proteinases resp onsible for aggrecan degradation in situ in articular cartilage are the agg recanases, 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 monoclona l antibody technologies to identify catabolic neoepitopes on aggrecan degra dation products; (ii) the use of such neoepitope antibodies in studies desi gned to characterise and identify the enzymes responsible for cartilage agg recan metabolism; (iii) the biochemical properties of soluble cartilage agg recanase(s) and their differential expression in situ; and (iv) model cultu re systems for studying cartilage aggrecan catabolism. These studies have c learly established that 'aggrecanase(s)' is primarily responsible for the c atabolism and loss of aggrecan from articular cartilage in the early stages of arthritic joint diseases that precede overt collagen catabolism and dis ruption of the tissue integrity. At later stages, when collagen catabolism is occurring, there is evidence for MMP-mediated degradation of the small p roportion of aggrecan remaining in the tissue, but this occurs independentl y of continued aggrecanase activity. Furthermore, the catabolism of link pr oteins by MMPs is also initiated when overt collagen degradation is evident . (C) 2000 Elsevier Science B.V./International Society of Matrix Biology. A ll rights reserved.