Fig. 1. Metalloproteinase inhibitors in the pericellular environment. (A) Tissue inhibitors of metalloproteinases (TIMPs). TIMPs-1-4 are largely matrix metalloproteinase (MMP) inhibitors modulating the activity of soluble, matrix bound and cell associated MMPs. TIMP-3 is an extracellular matrix protein, probably bound to heparan sulphate proteoglycans and is a potential inhibitor of the function of some membrane-associated ADAM s (a disintegrin and a metalloproteinase), as well as the matrix-associated ADAM-TS (ADAM-thrombospondins, not shown). TIMP-2 acts in conjunction with MT1-MMP as a receptor for the pro-form of MMP-2 at the cell surface, allowing an efficient activation and focussing of the active form of this soluble proteinase. In some cell types, TIMP-1 and TIMP-2 may have receptors directly linked to intracellular signalling pathways regulating cell behaviour. (B) Other inhibitors. RECK (reversion inducing cysteine rich protein with Kazal motifs) is a GPI-anchored glycoprotein that binds and inhibits a number of MMPs. The pan proteinase inhibitor 2-macroglobulin, although very large, has some access to the pericellular space in vascularised tissues and may be involved in MMP endocytosis through the low density lipoprotein receptor-related protein (LDL-RP). The roles of the LDL-RP in MMP2 removal via a thrombospondin-2 (TSP-2) complex and in direct MMP9 removal have been described. The tissue factor pathway inhibitor (TFPI-2) has also been described as an MMP binding agent