Mechanisms of proteoglycan metabolism that lead to cartilage destruction in the pathogenesis of arthritis.
The mechanisms and agents involved in cartilage matrix destruction are poorly understood and at present there are no means of therapeutic intervention that halt or slow the degradative processes that result in tissue loss, joint space narrowing and the eventual need for surgery with total joint replacement. In recent years our laboratory has pioneered the development and use of monoclonal antibody (MAb) technologies for the study of changes in cartilage matrix metabolism in health and disease. In this chapter we have summarized results coming from our recent studies examining the mechanisms of cartilage proteoglycan (aggrecan) catabolism that precedes cartilage destruction in arthritis. This research has used two approaches. The first is our access to a panel of MAbs that recognize both constitutive structural epitopes and catabolic neoepitopes on cartilage proteoglycan metabolites. These antibodies have allowed us to determine whether the unknown proteolytic agent 'aggrecanase' or known matrix metalloproteinases (MMPs) are involved in the increased aggrecan catabolism that is observed in arthritis. Secondly, we have used reverse transcription-polymerase chain reaction (RT-PCR) techniques to profile the expression of members of the MMP family or ADAMs (A disintegrin and metalloproteinase) that are potentially involved in this degenerative process. Collectively, these investigations have established that aggrecanase is the major proteolytic activity responsible for aggrecan loss in the early stages that lead to cartilage degradation in arthritis. In addition, our studies have allowed us to determine many important biochemical 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 stages of cartilage destruction that lead to surface fibrillation. However, MMPs 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 matrix proteases. Furthermore, we have observed changes in the patterns of cartilage 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.
Caterson
B
B
Connective Tissue Biology Laboratories, Cardiff School of Biosciences, Cardiff University, Wales, UK.
Flannery
C R
CR
Hughes
C E
CE
Little
C B
CB