Matrix metalloproteinase and aggrecanase generated aggrecan fragments: implications for the diagnostics and therapeutics of destructive joint diseases

The degradation of extracellular matrix (ECM) components of articular cartilage is a hallmark of joint-destructive diseases like osteoarthritis (OA) and rheumatoid arthritis (RA). A major component of the ECM is aggrecan, a proteoglycan, which is among the first matrix components to be degraded by the action of catabolic enzymes, increasingly expressed and activated during the inflammatory responses accompanying the aforementioned joint-diseases. The two main families of enzymes are Matrix Metalloproteinases (MMPs) and aggrecanases, which both contribute to the degradation of the ECM, although their relative importance may vary between matrix components. Understanding the process of aggrecan degradation has crucial implications for improving the early diagnosis and monitoring of destructive joint-diseases, as well as the therapeutic responses to disease-modifying agents with potential chondroprotective effects. In the present review, we wish to provide an update on the emerging knowledge in the field obtained from ex vivo cartilage explants subjected to catabolic enzymes relevant for the pathogenesis of osteoarthritis (OA), as well as from synovial fluid of OA patients. In addition, we discuss the present status of specific immunochemical biomarker assays that were recently introduced to serve as diagnostic tools and emerging concepts of pharmacological interventions targeting the inhibition of aggrecan destruction, with the ultimate aim of decreasing the epidemiological burden of OA and rheumatoid arthritis (RA). Drug Dev Res 68:1–13, 2007. © 2007 Wiley-Liss, Inc.