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doi: 10.1242/10.1242/jcs.00063
Commentary |
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
Author for correspondence (e-mail:
gm290{at}cam.ac.uk)
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.
2-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.
Key words: MMP, TIMP, RECK, Therapy
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