Mechanisms of proteoglycan metabolism that lead to cartilage destruction in the pathogenesis of arthritis

The mechanisms and agents involved in cartilage matrix destruction are poor ly understood and at present there are no means of therapeutic intervention that halt or slow the degradative processes that result in tissue loss, jo int space narrowing and the eventual need for surgery with total joint repl acement. In recent years our laboratory has pioneered the development and u se of monoclonal antibody (MAb) technologies for the study of changes in ca rtilage matrix metabolism in health and disease. In this chapter we have su mmarized results coming from our recent studies examining the mechanisms of cartilage proteoglycan (aggrecan) catabolism that precedes cartilage destr uction in arthritis. This research has used two approaches. The first is ou r access to a panel of MAbs that recognize both constitutive structural epi topes and catabolic neoepitopes on cartilage proteoglycan metabolites. Thes e antibodies have allowed us to determine whether the unknown proteolytic a gent 'aggrecanase' or known matrix metalloproteinases (MMPs) are involved i n the increased aggrecan catabolism that is observed in arthritis. Secondly , we have used reverse transcription-polymerase chain reaction (RT-PCR) tec hniques to profile the expression of members of the MMP family or ADAMs (A disintegrin and metalloproteinase) that are potentially involved in this de generative process. Collectively these investigations have established that aggrecanase is the major proteolytic activity responsible for aggrecan los s in the early stages that lead to cartilage degradation in arthritis. In a ddition, our studies have allowed us to determine many important biochemica l properties of aggrecanase without knowing the identity of the enzyme. Our data also calls into question the role that MMPs may play in the early sta ges of cartilage destruction that lead to surface fibrilation. However, MMP s may be involved in later stages where collagen degradation is prevalent. The role that ADAMs play is still unknown, although they are postulated to play an important role in shedding or activation of different classes of ma trix proteases. Furthermore, we have observed changes in the patterns of ca rtilage expression in fresh tissue and model culture systems. This work has indicated clearly that there are several different classes of enzyme that can be targeted for innovative therapies which could slow or halt cartilage destruction in arthritis. (C) 1999 Prous Science. All rights reserved.