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doi: 10.1242/10.1242/jcs.00063

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Metalloproteinase inhibitors: biological actions and therapeutic opportunities

Andrew H. Baker¹, Dylan R. Edwards² and Gillian Murphy^2,*,

¹ BHF Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK
² School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK
^* Present address: Department of Oncology, Cambridge University, Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK

View larger version (32K): [in a new window]   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

View larger version (33K): [in a new window]   Fig. 2. Mechanistic aspects of TIMP-3 gene therapy. Highly efficient replication-deficient adenoviral vectors engineered to express TIMP-3 infect cells through receptor-mediated endocytosis, traffic to the nucleus and use the host DNA machinery to transcribe and secrete TIMP-3. Recombinant TIMP-3 binds the ECM where it initiates its desired phenotypic effects on cells (indicated by 1-3 in green). TIMP-3 overexpression is associated with anti-angiogenic activity (1), reduction in cell migration and invasion (2) and initiation of apoptosis (3), mediated through modulation of MP activity. The induction of apoptosis occurs though modulation in death receptor/death ligand activity at the cell surface resulting in activation of caspases (in blue). Apoptosis is mediated through a type-2-dependent pathway involving caspase-8, -9 and -3 as well as mitochondrial components. Ultimately, caspase-3-mediated cleavage of death substrates leads to apoptosis.