Fig. 1.

Extracellular regulation of cartilage-degrading metalloproteinase activities. Metalloproteinases are regulated in the extracellular environment by a number of mechanisms, including proteolytic activation of zymogens (a), interaction with endogenous inhibitors (TIMPs and α2M)(A), endocytic clearance mediated by cell surface scavenging receptor LRP1 (b), binding to the cell surface molecules and ECM via sulphated GAGs (c). Sulphated GAGs inhibit ADAMTSs activity by two modes of action including interacting with their ancillary domains and increasing TIMP-3 affinity for ADAMTSs (c). LRP1 and sulphated GAGs can compete each other for binding to several metalloproteinases and TIMP-3 (b and c)