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)
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Summary |
---|
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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Introduction |
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|
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Tissue inhibitors of metalloproteinases (TIMPs): basic structure and activity |
---|
|
The TIMPs have molecular weights of 21 kDa and are variably
glycosylated (Table 1). They
have six disulphide bonds and comprise a three-loop N-terminal domain and an
interacting three-loop C-subdomain. Most of the biological functions of these
proteins discovered thus far are attributable to sequences within the
N-terminal domain, although the C-subdomains mediate interactions with the
catalytic domains of some MMPs and with the hemopexin domains of MMP-2 and
MMP-9 (Brew et al., 2000
). The
TIMPs are secreted proteins, but may be found at the cell surface in
association with membrane-bound proteins; for example, TIMP-2, TIMP-3 and
TIMP-4 could bind MMP-14, a membrane-type (MT) MMP. Uniquely, TIMP-3 is
sequestered to the ECM by binding to heparan-sulphate-containing proteoglycans
and possibly chondroitin-sulphate-containing proteoglycans
(Yu et al., 2000
). All four
TIMPs inhibit active forms of all MMPs studied to date, their binding
constants being in the low picomolar range, although TIMP-1 is a poor
inhibitor of MMP-19 and a number of the MT-MMPs
(Table 1). TIMPs have no
significant activity against the astacins (J. Bond, personal communication),
but some activity of TIMP-3 (and to some extent TIMP-1) against the ADAMs has
been shown. TIMP-3 inhibits ADAM 12 and ADAM 17 and the aggrecan-degrading
enzymes ADAM-TS4 and ADAM-TS5, and TIMP-1 inhibits ADAM 10. Here, dissociation
constants are in the subnanomolar range
(Amour et al., 2000
;
Amour et al., 1998
;
Kashiwagi et al., 2001
).
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Phenotypic effects of TIMPs |
---|
TIMP-2 is thought to act through specific, saturable high-affinity
receptors (Kd 0.15 nM) and links to G protein and
cAMP signalling pathways (Corcoran and
Stetler-Stevenson, 1995
). Since reduced and alkylated TIMP-2 is
mitogenic (Hayakawa et al.,
1994
) and an inactive mutant that has an additional N-terminal
alanine residue promotes fibroblast growth
(Wingfield et al., 1999
),
these activities are probably distinct from its ability to inhibit MMPs.
Importantly, some TIMPs are associated with the tumour progression
(Grignon et al., 1996
;
Jiang et al., 2001
;
Kossakowska et al., 1991
;
Stetler-Stevenson et al.,
1997
), although, paradoxically, others suppress tumour formation
(Ahonen et al., 1998
;
Baker et al., 1999
;
Bian et al., 1996
;
Edwards et al., 1996
)
(Table 1). TIMPs also have
divergent effects on programmed cell death. In Burkitt's lymphoma cell lines,
high TIMP-1 expression correlates with the increased expression of activation
and survival markers, and TIMP-1 confers resistance to Fas-ligand-dependent
and -independent apoptosis (Guedez et al.,
1998
). Conversely, TIMP-2 can promote apoptosis in an in vivo
colorectal cancer model (Brand et al.,
2000
) but protects B16 melanoma cells from apoptosis
(Valente et al., 1998
). High
levels of TIMP-3 promote apoptosis in many cell types in vitro and in vivo
(Ahonen et al., 1998
;
Baker et al., 1998
;
Bond et al., 2000
;
Smith et al., 1997
;
Yang and Hawkes, 1992
), and
this effect is associated with death receptor modulation
(Bond et al., 2002
;
Smith et al., 1997
). It is not
clear whether TIMP-3-induced apoptosis has any physiological parallel. In
normal development, high-level TIMP-3 expression occurs in uterine decidual
cells during embryo implantation and has been linked with the survival of
these differentiated cells (Alexander et
al., 1996
). TIMP-4 can also instigate apoptosis in transformed
cardiac fibroblasts but inhibits apoptosis in human breast cancer cells in
vitro and mammary tumours in vivo; it is thus a tumour promoter when
overexpressed. The elucidation of the mechanisms involved in controlling these
distinctly opposing phenotypic effects of TIMPs is of paramount importance if
we are to understand TIMP biology and assess the potential therapeutic roles
of these proteins (see below).
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TIMP-knockout phenotypes |
---|
![]() |
TIMP-like molecules |
---|
Thrombospondin-2 is another MMP inhibitor. It can regulate MMP-2 by forming
a complex that facilitates scavenger-receptor-mediated endocytosis. Similarly,
thrombospondin-1 has been shown to inhibit proMMP-2 and proMMP-9 activation
and modulate MMP-2 production (Egeblad and
Werb, 2002).
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---|
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Reversion inducing cysteine-rich protein with Kazal motifs: RECK |
---|
![]() |
Development of TIMPs as therapeutic molecules |
---|
![]() |
MMP blockade and cardiovascular disease |
---|
Many MPI studies have been performed in acute cardiovascular complaints,
particularly restenosis and vein graft failure. These applications offer the
opportunity to prevent disease progression in a time frame that is applicable
to the current technologies available to gene therapists, by high-level
transient TIMP overexpression locally within the vasculature. Post-balloon
angioplasty procedures (although dwindling in frequency owing to use of
stents, which act as scaffolds to hold arteries open) were an obvious target
for TIMP gene therapy. MPs were envisaged to play an integral role in the
pathological development of restenotic lesions, which are mediated by the
proliferation and migration of vascular smooth muscle cells
(Bendeck et al., 1994;
Southgate et al., 1996
;
Zempo et al., 1994
). However,
small molecule MMP inhibitors fail to prevent restenosis, even though they
efficiently block early smooth muscle cell migration
(Bendeck et al., 1996
).
Recently, the broad spectrum MP inhibitor RO113-2908 failed to prevent
angioplasty- or stent-induced intermal hyperplasia over 4 weeks in
atherosclerotic primates (Cherr et al.,
2002
), although MP inhibitors do reduce constrictive remodeling in
a porcine angioplasty model (de Smet et
al., 2000
). Similarly, TIMP overexpression
(Cheng et al., 1998
;
Dollery et al., 1999
;
Forough et al., 1996
)
prevented smooth muscle cell migration but long-term benefits were not fully
established. Vein graft failure, in common with restenosis, involves smooth
muscle cell migration and proliferation as a central mechanism, and increased
MP synthesis and activation have been observed in appropriate models
(George et al., 1997
;
Southgate et al., 1999
). Local
overexpression of TIMPs (TIMP-1, TIMP-2 or TIMP-3) in a human vein graft model
prevented MMP-induced neointima formation
(George et al., 1998a
;
George et al., 1998b
;
George et al., 2000
). In vivo,
overexpression of TIMP-3, but not other TIMPs, significantly inhibited disease
progression through its ability to promote apoptosis
(George et al., 2000
). This is
an important demonstration of how unique attributes of individual TIMPs can be
used to therapeutic advantage.
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Cancer |
---|
There are, however, safety issues relating to the biological effects of
TIMPs and, in particular, their growth promoting activity. This paradigm is
highlighted by two recent studies. First, Celiker et al. delivered a DNA
plasmid encoding TIMP-4 via intra muscular injection into nude mice with
tumours derived from G401 Wilm's tumor cells. They observed a significant
reduction in tumour growth through the elevation of circulating TIMP-4 and
uptake of the transgene into tumour cells. These effects were observed at
TIMP-4 levels below the level required for MMP inhibition
(Celiker et al., 2001).
However, when the same transgene, route of delivery and nude mouse model were
used to investigate breast cancer growth, TIMP-4 stimulated tumorigenesis
through an MMP-independent anti-apoptotic activity
(Jiang et al., 2001
). Clearly
different cancers were under investigation but the antiapoptotic/pro-survival
effects of TIMPs have also been defined for TIMP-1 in B-cell lymphoma
(Guedez et al., 1998
) and
Hodgkin/Reed-Sternberg cells (Oelmann et
al., 2002
).
The biological characteristics of TIMP-3 have also been exploited in cancer
gene therapy (Fig. 2). As
previous studies have shown, TIMP-3 inhibits local invasion of cancer cells,
promotes apoptosis, inhibits angiogenesis
(Anand-Apte et al., 1997) and
binds locally to the ECM (Leco et al.,
1994
), which suggests that overexpression of TIMP-3 is a rational
multiphenotypic approach for localised destruction of cancerous tissue.
Indeed, a recent study has demonstrated this potential
(Ahonen et al., 2002
). TIMP-3
overexpression in melanomaderived subcutaneous tumours in nude mice reduced
gelatinolytic MMP activity, reduced blood vessel density, promoted apoptosis
and significantly reduced tumour growth. Importantly, in side-by-side
comparative studies, TIMP-3 overexpression was significantly better than
overexpression of p53 (Ahonen et al.,
2002
). Such studies use the attributes of individual TIMP
molecules to therapeutic benefit and may, in the longer term, show promise for
cancer gene therapy in the clinic.
|
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Concluding remarks |
---|
![]() |
Acknowledgments |
---|
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