The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review.

Destruction of articular cartilage is a key feature of a number of arthritides, osteoarthritis prominent among them. Aggrecan degradation, caused by increased activity of proteolytic enzymes that degrade macromolecules in the cartilage extracellular matrix, is followed by irreversible collagen degradation. The degradation of aggrecan is mediated by various matrix proteinases, mainly the aggrecanases, multidomain metalloproteinases belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. There has been much interest in the possible role of these aggrecanases, mainly ADAMTS4 and ADAMTS5, as therapeutic targets in osteoarthritis. There is still debate which of them is the major aggrecanase in osteoarthritis, however, as well as major issues concerning how they are regulated, with possible discrepancies between murine models and results obtained using human osteoarthritis tissue. This review discusses some recent data regarding the regulation of ADAMTS4 and ADAMTS5 gene expression in osteoarthritis, with emphasis on the role of proinflammatory cytokines in driving these enzymes, and of the transcription factor NFkappaB in mediating their expression.