Metalloproteinase inhibitors: biological actions and therapeutic opportunities.
Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the matrix metalloproteinase (MMP) sub-family, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation. Other proteins have modest inhibitory activity against some of the MMPs, including domains of netrins, the procollagen C-terminal proteinase enhancer (PCPE), the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and tissue factor pathway inhibitor (TFPI-2), but their physiological significance is not at all clear. Alpha2-macroglobulin, thrombospondin-1 and thrombospondin-2 can bind to some MMPs and act as agents for their removal from the extracellular environment. In contrast, few effective inhibitors of other members of the metzincin family, the astacins or the distintegrin metalloproteinases, ADAMs have been identified. Many of these MMP inhibitors, including the TIMPs, possess other biological activities which may not be related to their inhibitory capacities. These need to be thoroughly characterized in order to allow informed development of MMP inhibitors as potential therapeutic agents. Over activity of MMPs has been implicated in many diseases, including those of the cardiovascular system, arthritis and cancer. The development of synthetic small molecule inhibitors has been actively pursued for some time, but the concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.
Baker
Andrew H
AH
BHF Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK.
Edwards
Dylan R
DR
Murphy
Gillian
G
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D002462:Cell Membrane / Q000201:enzymology; D005057:Eukaryotic Cells / Q000201:enzymology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism* / Q000627:therapeutic use*; D000511:alpha-Macroglobulins / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D011993:Recombinant Fusion Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D000511:alpha-Macroglobulins; D020782:Matrix Metalloproteinases