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Editor: Michael M. Cox
Crit Rev Biochem Mol Biol, 2013; 48(3): 222272
! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/10409238.2013.770819
REVIEW ARTICLE
Abstract
Keywords
20
13
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Belgium
Introduction
Gelatinase B/MMP-9
DOI: 10.3109/10409238.2013.770819
MMP-9
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Figure 1. Evolution of the PubMed literature on all MMPs, MMP-2, MMP-9, ATPsynthase, t-PA and caspases. The past decades, MMPs have
been increasingly studied. Following a contemplation period after the turn of the century, MMPs again attract attention and curiosity. MMP-2
and MMP-9, the two gelatinases, are the most studied MMPs. In comparison, the caspases are another enzyme family with caspase-3 being most
publicized.
development of new technologies and applications. In comparison with academia, industry has somewhat lost interest
in matrix metalloproteinases (MMPs) as druggable targets a
decade ago (Coussens et al., 2002). Possibly this is based
on expectations of obtaining a lucky strike, rather than on
critically analyzing obtained data to make the right choices
for industrial success. Excellent MMP inhibitors have been
developed meanwhile and all the present-day omics tools
provide us with clearer views on expression, regulation and
eventually altered activities of MMPs in pathological versus
normal conditions. These elements are stepping stones for
renewed industrial interests.
It is clear that applications of MMP inhibitors and MMP
diagnostics in vascular and inflammatory diseases are
approaching (Hu et al., 2007). Cancer therapy with MMP
inhibitors may also revive, when with the aid of new
technologies a broader, wider and deeper picture of what
happens in the tumor micro-environment is casted (Gerg
et al., 2008; Kruger et al., 2010; Nakasone et al., 2012;
Overall & Kleifeld, 2006).
The progress in fact revival and the shortcomings in
MMP research are best illustrated by comparisons of all MMP
literature in PubMed and that of some well-studied enzymes:
ATPsynthase (Lau & Rubinstein, 2012; von Ballmoos
et al., 2008), tissue-type plasminogen activator and the
caspases. ATPsynthase is an excellent example of a multidomain enzyme attracting multidisciplinary interests, ranging
from chemistry to biochemistry, from molecular biology
to physiology and from genetics to endocrinology. Tissue
plasminogen activator (t-PA) is an important example of
a proteinase that gained status from its clinical use in
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J. Vandooren et al.
MMP
Locus
Gelatinase B
20q11.2-q13.1
Gelatinase A
16q13-q21
Collagenases
1, 8, 13
11q22.3
14
15
16
17
24
25
14q11-q12
16q13
8q21.3
12q24.3
20q11.2
16p13.3
MT-MMPs
Stromelysins
Matrilysins
3, 10
11
7
26
signal peptide
propeptide
active site
Zn2+-binding domain
hemopexin domain
fibronectin repeats
O-glycosylated domain
membrane anchor
11q22.3
22q11.23
11q21-q22
11p15
Figure 2. The modular domain structure of prototypic MMP family members. The MMPs are ordered by decreasing domain complexities and
their chromosomal locations in the human genome. Genome locations were obtained from the Entrez Gene Database (Maglott et al., 2011). The color
codes for individual domains will be used throughout the whole manuscript and is the same in all figures.
DOI: 10.3109/10409238.2013.770819
Gelatinase B/MMP-9
225
Figure 3. Amino acid sequence of MMP-9 with the indication of demonstrated posttranslational modifications by N-linked glycosylation, cysteine
bridging, oligomerization and proteolytic truncation, including activation of the zymogen form. All these processes are executed by enzymatic
reactions. The attachment of multiple O-linked oligosaccharides on the O-glycosylated domain is not indicated because site-specific annotation is not
yet known. The two free cysteine residues (in the O-glycosylated domain and in the hemopexin domain, indicated in red) are the candidates for the
formation of oligomers and covalent complexes with neutrophil gelatinase B-associated lipocalin (NGAL or lipocalin 2). Color code of domains is the
same as in Figure 2. a; meprin a, b; meprin b, NE; neutrophil elastase, b-hem; b-hematin, KK; tissue kallikrein, KLK7; kallikrein-related peptidases 7.
226
J. Vandooren et al.
DOI: 10.3109/10409238.2013.770819
Gelatinase B/MMP-9
227
Figure 4. The multidomain structure of MMP-9. The following MMP-9 domains are shown; the propeptide (green), the active site (yellow), the three
fibronectin repeats (blue), the metal binding site (orange) with the catalytic zinc ion (grey), the OG domain (brown) and the PEX domain (red). Three
different representations are shown. Panel A; model of MMP-9 from 2001 (Opdenakker et al., 2001b). Panel B; A refined model for MMP-9, based on
compositional and site-specific glycan analysis and sedimentation data, generated by Dr. Mark Wormald, Oxford University Glycobiology Institute
(Van den Steen et al., 2006). Panel C; a contour model of one MMP-9 conformation based on the observations made with the use of atomic force
microscopy and SAXS analysis (Rosenblum et al., 2007b). The colored protein segments are based on the analysis of the two presently available crystal
structures of MMP-9 (PDB ID: 1L6J and 1ITV). It needs to be emphasized that the O-glycosylated domain and its attached oligosaccharides yield
molecular flexibility and heterogeneity. As a consequence, the picture represents one conformation of many possible shapes. Panel D; cartoon model,
illustrating the fingertip interaction between the aminoterminus of the prodomain with the third fibronectin repeat, the flexibility of the O-glycosylated
domain, the structural separation of the catalytic part and the hemopexin domain and the open spaces occupied by highly mobile oligosaccharides
(not indicated). The color code for the indication of domains is the same as in Figures 2 and 3.
228
J. Vandooren et al.
Gelatinase B/MMP-9
229
DOI: 10.3109/10409238.2013.770819
Figure 5. Domain structure of MMP-9 and details of the propeptide. The propeptide contains the cysteine switch consensus sequence PRCXXPD
(underlined) which contains Cys99 with which it blocks the enzyme active site. The propeptide sequence is subject to several types of posttranslational
modifications including N-glycosylation. The secondary structure of the propeptide consists of three perpendicular a-helices. At the aminoterminus,
the propeptide has hydrophobic interactions and forms a hydrogen bridge with residues from the third fibronectin repeat. Centrally, the domain tightly
interacts with the active site and the metal binding site (Elkins et al., 2002).
230
J. Vandooren et al.
Complexes
Neutrophil gelatinase-associated lipocalin (NGAL) in association with MMP-9 is the best known heteromeric complex
of MMP-9. In the human species, it has a molecular weight
of 125 kD and is formed by covalent linkage of MMP-9
and NGAL (Triebel et al., 1992). NGAL belongs to the
superfamily of lipocalins (Kjeldsen et al., 1993), which
are biochemical markers for a variety of diseases (Xu &
Venge, 2000). The NGAL/MMP-9 complex is mainly
secreted by neutrophils. Possibly for these reasons, the
NGAL/MMP-9 complex is useful as a maker for several
diseases (Hatipoglu et al., 2011; Tsai et al., 2011).
Functionally, complex formation with NGAL is thought to
protect MMP-9 from proteolytic degradation (Yan et al.,
2001b). Another high-molecular weight (300 kDa) MMP-9
complex is produced by human macrophages. As mentioned
above, the leukemic macrophage cell-line THP-1 secretes
a MMP-9/CSPG complex (Winberg et al., 2000) with altered
biochemical properties (Malla et al., 2008).
Truncated forms
Besides the active 82 kDa MMP-9 (Ogata et al., 1992),
MMP-3 also generates a 65 kDa form of MMP-9, lacking both
the aminoterminal propeptide and the carboxyterminal
hemopexin domain (Okada et al., 1992). Since the carboxyterminal domains of MMP-9 are required for a high affinity
binding with the natural inhibitor TIMP-1 (OConnell et al.,
1994), 65 kDa MMP-9 is able to escape inhibitor control.
65 kDa MMP-9 has been purified from body fluids and was
less susceptible to inhibition by TIMP-1. In addition, KLK7
and meprin-a are also able to remove the carboxyterminal
domains from MMP-9 (Bellini et al., 2012; Geurts et al.,
2012a; Ramani et al., 2011).
DOI: 10.3109/10409238.2013.770819
Gelatinase B/MMP-9
231
PPAR-g agonist, inhibition of ERK and activation of GSK-3b, results in reduced expression of MMP-9
Inhibition of the RhoA/ROCK pathway but increased MMP-9 mRNA levels
Inhibition of expression
Induces MMP-9 expression
Induces expression of MMP-9
T-cell binding to VCAM-1, mediated through a4b2 integrin
Induces MMP-9
Rosiglitazone
Simvastatin
Tetracyclins
TGF-b
TNF-a
VCAM-1
VEGF
Inhibition of secreted levels of MMP-9, was suggested to involve destabilization of the actin cytoskeleton
Simvastatin
Regulation of activation
B-hematin
References
J. Vandooren et al.
Low O2 level
OA-NO2
oxLDL
PN-1
Radiation
RECK
MMP-3
LTA
LZAP
Melatonin
MMP-1
Induces MMP-9 production through activation of ERK, p38, mitogen-activated protein and NF-kB
Stabilizes MMP-9 mRNA upon induction with IL-1b
Represses the transcription factor ETV4
Inhibits p38 phosphorylation and thereby blocks the p38 signaling pathway
Bind to FXR and MMP-9 promoter region
Decreases expression of MMP-9 through inhibition of AP-1
Induces MMP-9
Edaravone
Fibronectin
Galectin-7
GnRH
HCMV infection
Histamine
Hyperforin
IL-13
IL-1b
Regulators of transcription
AGE
ATPgS
ATXN1
Berberine
Bile acids
CCOS
EMMPRIN/CD147
Regulator
232
Crit Rev Biochem Mol Biol, 2013; 48(3): 222272
References
AGE: advanced glycation end product, AP-1: activator protein 1, APMA: 4-aminophenylmercuric acetate, ATPgS: Adenosine 50 -O-(3-thio)triphosphate, CaM: Calmodulin, CaMKII: Ca2/calmodulin-dependent
protein kinases II, CCOS: carboxylated chito-oligosaccharides, COX: cyclo-oxygenase, EP4: Prostaglandin E receptor 4, ERK: extracellular-signal-regulated kinases, FXR: Farnesoid X receptor, GnRH:
gonadotropin-releasing hormone, GSH: Glutathione, GSK-3b: Glycogen synthase kinase-3 beta, H1R: Histamine H1 Receptor, HCMV: Human cytomegalovirus, HClO: hypochlorous acid, HIF: hypoxia
inducible factor-, IL-: Interleukin-, JNK: c-Jun N-terminal kinases, LTA: lipoteichoic acid, MCF-7: Michigan Cancer Foundation7, NAC: N-acetylcysteine, NE: neutrophil elastase, NF-kB: nuclear factor
kappa-light-chain-enhancer of activated B cells, NO: Nitric oxide, OA-NO2: Nitro-oleic acid, oxLDL: oxidized low-density lipoprotein, PDGFR: platelet-derived growth factor receptor, PDI: protein disulfide
isomerase, p-ERK: phosphorylated ERK, PGE2: prostaglandin E2, PI3K: Phosphoinositide 3-kinase, PN-1: protease nexin-1, PPARg: peroxisome proliferator-activated receptor-g, RECK: reversion-inducing
cysteine-rich protein with kazal motif, RhoA: Ras homolog gene family, member A, ROCK: Rho-associated protein kinase, SHP-2: Src Homology protein-2, TGF-b: Transforming growth factor beta, TIMP-1:
tissue inhibitor of metalloproteinases-1, TNF-a: tumor necrosis factor alpha, uPA: urokinase-type plasminogen activator, VCAM-1: vascular cell adhesion molecule 1.
This table is an extension of information provided in an other review (Van den Steen et al., 2002a).
Tetracyclins
TNF-a
Plasmin/plasminogen
GSH
HClO
Melatonin
Meprins
MMP-3
MMP-26
NAC
NE
NO
OA-NO2
Regulator
DOI: 10.3109/10409238.2013.770819
Gelatinase B/MMP-9
233
234
J. Vandooren et al.
Cell type
Astrocytes (RBA-1)
B-CLL cells
Bladder cancer cells
(HTB9, HTB5)
Breast cancer cells (MCF-7,
MDA-MB-231, 168FARN)
Cardiac myofibroblasts
Endothelial cells (HUVEC)
Hepatocellular carcinoma cells
(HCC)
Keratinocytes
(MK cells, HaCaT Cells)
Location of MMP-9
Cytosol, cell membrane, nucleus
and associated with the cytoskeleton (actin and microtubules), LAMP-2, molecular
motor proteins (myosin V,
kinesin). Secreted in 400500 nm vesicles with or without
TIMP-1
On cell membrane and in podosomes, found in cell lysates and
cell culture medium
Secreted into cell culture medium,
in an SHP-2-dependent way
Secreted into cell culture medium
References
P38 MAPK/MAPKAPK2
signaling
IL-1b, alternatively spliced CD99,
PN-1
TNFa
Simvastatin
Bile acids
Radiation, LPA
GnRH
Schwann cells
Stem cells
Smooth muscle cells (VSMC,
HASMC)
Decreased O2 levels
OxLDL
Rosiglitazone
B-CLL; B-cell chronic lymphocytic leukemia, CD99; cluster of differentiation 99, CXCL; CXC chemokine ligand, CXCR; CXC chemokine receptor,
ERK; extracellular-signal-regulated kinases, GnRH; gonadotropin-releasing hormone, HaCaT; cultured human keratinocyte, HASMC; human aortic
smooth muscle cells, HCC; hepatocellular carcinoma, HCMV; human cytomegalovirus, HUVEC; human umbilical vein endothelial cell, HTB;
heterotopically transplanted rat urinary bladder, IFN-g; interferon-g, IL-; interleukin-, IR; infra-red light, LAMP-1; lysosomal-associated membrane
protein 1, LPA; Lysophosphatidic acid, LPS; lipopolysaccharide, MAPK; mitogen-activated protein kinase, MAPKAPK; MAPK-activated protein
kinase, MCF-7; Michigan Cancer Foundation7, MEK; MAPK or Erk kinases, MK; mouse keratinocyte, MPM; mouse peritoneal macrophages,
oxLDL; oxidized low-density lipoprotein, PDI; protein disulfide isomerase, PN-1; protease nexin-1, RAB27a; Ras-related protein, SHP-2;
Src Homology protein-2, TGF-b; Transforming growth factor beta, TLA; lipoteichoic acid, RBA; rat brain astrocytes, TIMP-1; tissue inhibitor
of metalloproteinases-1, TNF-a; tumor necrosis factor alpha, VCAM-1; vascular cell adhesion molecule 1, VSMC; vascular smooth muscle cell.
This update complements a previous review (Van den Steen et al., 2002a) and is not exhaustive.
DOI: 10.3109/10409238.2013.770819
Regulation by cytokines
A number of studies have reinforced earlier findings from
1991 that cytokines induce MMP-9 production (Masure et al.,
1991; Opdenakker et al., 2001b). For instance, the invasive
potential of human breast cancer cells was enhanced by
adding IL-1b which acts through an SHP-2-dependent
signaling pathway. Activation of this pathway results in
higher levels of secreted MMP-9 (Wang et al., 2005). As
outlined above, also in bronchial epithelial cells, MMP-9
expression can be activated by the activation of NF-kB,
whereas PPAR activators were shown to inhibit the
expression of MMP-9 by counteracting NF-kB (Shishodia
et al., 2003).
Synergy and antagonism within the cytokine network
determine the immunological and physiological outcomes.
Gelatinase B/MMP-9
235
Figure 7. Illustration of the different levels of MMP-9 regulation. At the transcriptional level MMP-9 is regulated by several pathways including
the Smad pathway, the MAPK pathway, the NIK/NEMO/IKK pathways, the STAT pathways and nuclear receptor pathways. The MMP-9 promoter
region has several regulatory elements, including AP-1 and NF-kB. Upon transcription, dynamic mRNP complexes control mRNA degradation
and stabilization, e.g. with the help of nucleolin. Once secreted, proMMP-9 is activated into MMP-9 by proteases such as MMP-3, plasmin
and trypsin. Futhermore, MMP-9 binds to several cell surface molecules, e.g. Ku, LRP1/2, integrins and CD44, forming an MMP-9 cell surface
complex.
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J. Vandooren et al.
Gelatinase B/MMP-9
DOI: 10.3109/10409238.2013.770819
237
Site
type
hsa-miR-3713
PC
hsa-miR-1224-3pA
hsa-miR-4690-3pA
hsa-miR-3123A
hsa-miR-1286A
hsa-miR-330-3pA
hsa-miR-183A
hsa-miR-4802-3pA
hsa-miR-4666-5pA
hsa-miR-4450A
hsa-miR-491-5pA,B
PC
PC
PC
PC
PC
V
PC
PC
PC
M
hsa-miR-4281A
hsa-miR-133bA
hsa-miR-133aA
hsa-miR-296-3pA
miRNA
A
Size
Predicted position
(of 30 UTR)
Total context
score
8mer
7380
0.39
C
C
C
PC
PC
PC
PC
PC
PC
PC
7mer-m8
7mer-m8
8mer
7mer-m8
7mer-m8
7mer-m8
7mer-A1
7mer-A1
8mer
7mer-m8
117123
120126
179186
814
1218
2228
2531
2632
3239
3440
0.19
0.14
0.25
N/A
N/A
0.20
0.10
0.04
0.37
0.24
PC
V
V
M
PC
PC
PC
PC
7mer-A1
7mer-m8
7mer-m8
7mer-m8
4248
4349
4349
4753
0.21
0.11
0.11
0.12
hsa-miR-1915A
hsa-miR-2355-5pA
hsa-miR-3667-3pA
PC
PC
PC
PC
PC
PC
7mer-m8
8mer
7mer-A1
5056
5259
5662
0.23
0.33
0.10
hsa-miR-4448A
hsa-miR-149A
PC
M
PC
PC
7mer-m8
7mer-m8
5864
6167
0.15
0.20
hsa-miR-892bA
hsa-miR-4470A
hsa-miR-3149A
hsa-miR-4773A
hsa-miR-4691-5pA
hsa-miR-1238A
hsa-miR-3124-3pA
hsa-miR-204A
hsa-miR-211A
hsa-miR-4287A
hsa-miR-4685-3pA
hsa-miR-483-3pA
hsa-miR-1253A
hsa-miR-3613-3pA
hsa-miR-3065-5pA
hsa-miR-3145-5pA
hsa-miR-3691-3pA
hsa-miR-3925-5pA
hsa-miR-1303A
PC
PC
PC
PC
PC
PC
PC
V
V
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
7mer-m8
7mer-m8
7mer-A1
7mer-m8
8mer
7mer-A1
7mer-m8
7mer-m8
7mer-m8
7mer-m8
7mer-m8
7mer-m8
8mer
7mer-m8
7mer-m8
7mer-m8
7mer-A1
7mer-A1
7mer-m8
6268
6773
7682
9197
97104
99105
100106
103109
2228
104110
104110
109115
134141
148154
151157
155161
173179
180186
181187
0.18
0.13
0.01
0.14
0.33
0.08
0.02
0.07
0.07
0.15
0.15
0.14
0.25
0.02
0.12
0.24
0.16
0.10
0.18
hsa-miR-548mA
PC
PC
7mer-A1
187193
0.10
V; miRNA family broadly conserved among vertebrates, M; miRNA family conserved only among mammals, PC; poorly conserved, C; conserved,
7mer-m8; exact match to positions 28 of the mature miRNA, 7mer-A1; exact match to positions 27 of the mature miRNA followed by an A,
A
; predicted miR, B; experimentally identified miR.
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Gelatinase B/MMP-9
DOI: 10.3109/10409238.2013.770819
239
Activation of progelatinase B
The cysteine switch
An aminoterminal propeptide is present in all members of
the MMP family. It consists of approximately 80 amino acids
and caps the zinc-containing catalytic domain (Figure 5).
This propeptide domain contains the cysteine switch
PRCXXPD consensus sequence (Rosenblum et al., 2007a).
The cysteine switch explains the latency of pro-MMP-9 and
indicates that any means that can pull the cysteine99 away
from the Zn2 ion will result in activation and catalytic
activity. A decade ago it was already clear that activation
of MMP-9 occurs in a network of enzyme interactions.
At that time the following enzyme activators were described:
MMP-1, MMP-2, MMP-3, MMP-7, MMP-10, MMP-13,
MMP-26, trypsin, NE, cathepsin G and tissue kallikrein
(Van den Steen et al., 2002a). Meanwhile a number of new
details about gelatinase B activation have emerged and these
are briefly discussed here.
Occlusion of the active site by the propeptide domain and
coordination of the Zn2 with the sulfhydryl of Cys99 result
in a suppression of MMP activity. In vivo the MMP
zymogens are activated by proteases including kallikrein,
trypsin and other MMPs such as MMP-3 (Ogata et al.,
1992). In vitro this can also be achieved by chemical agents
such as aminophenyl mercuric acetate and other S-reactive
agents, reactive oxygen, detergents and heat. Since ROS are
also found in vivo, this is also a potential mechanism of
proMMP-9 activation, already described long ago (Peppin &
Weiss, 1986). Detergent-mediated denaturation, e.g. by SDS,
explains why pro-MMP-9 may be visualized by gelatin
zymography. If the SDS can be removed completely during
the renaturation process and pro-MMP-9 refolds completely,
then the zymogen form is not visible anymore on
zymography (Vandooren et al., 2013).
Zymogen activation releases the propeptide domain by
sequential proteolysis. When activated with MMP-3, the
first cleavage occurs in the loop connecting two helices of the
pro-peptide and the second cleavage occurs eight amino
acid residues downstream from the zinc-coordinated cysteine,
resulting in an active MMP (Ogata et al., 1992; Rosenblum
et al., 2007a). In the active MMP the Cys99 residue is
replaced by a H2O molecule. The group of Irit Sagi
(Rosenblum et al., 2007a) showed that stabilization of the
catalytic Zn2 ion (in three steps) is much faster than the
completion of the proteolytic event.
A graphical representation of the propeptide structure
and possible post-translational modifications is shown in
Figure 5. It is generally accepted that proMMP-9 is activated
by proteolytic cleavage of the propeptide. However, in line
with the effects of S-reactive reagents (see above), it has also
been demonstrated that proMMP-9 can be activated without
undergoing proteolysis (Bannikov et al., 2002).
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Gelatinase B/MMP-9
DOI: 10.3109/10409238.2013.770819
Human neutrophil elastase (HNE) activates or primes activation of proMMP-9 by introducing a cleavage between
Val58 and Ala59, Ala59 and Glu60 (Figures 3 and 5) in the
MMP-9 prodomain. In addition, HNE may degrade TIMP-1
and thereby inactivate the MMP-9 inhibition (Jackson
et al., 2010).
Priming of activation by meprins
Recently, activation of MMP-9 by meprin a and meprin b has
been described (Geurts et al., 2012a). Meprins are increasingly studied as convertases of proproteins, both in the
cytokine and in the protease fields (Jefferson et al., 2012;
Villa et al., 2003).
Meprin a was found to clip the tip of the gelatinase B
aminoterminus, thus destabilizing the proform (Figures 4
and 5). This resulted in priming for activation by MMP-3.
Remarkably, this meprin-mediated primed pro-MMP-9 form
corresponds with the natural protein produced by neutrophils
and for which the processing enzyme remained elusive for
20 years (Masure et al., 1991; Opdenakker et al., 1991a,b).
Furthermore, meprin also truncated MMP-9 at the carboxyterminus into a 68 kDa form. Maybe this form corresponds
to the 65 kDa hemopexin-less form described in earlier studies
(Bellini et al., 2012).
Inhibition of gelatinase B
Enzyme activity of MMPs leads to proteolysis of structural
(bone, cartilage) and functional (cytokines, hormones, receptors) molecules and these effects need to be tightly controlled
to keep the physiological balances in the host, whether this is
within the blood circulation or in tissues. The proteins
that execute these checks are inhibitors of MMPs such as
a2-macroglobulin in the circulation and the four specific
tissue inhibitors of MMPs (TIMP14). Several other proteins,
acting as inhibitors of MMPs, have gained attention. These
include the membrane-bound protein RECK (Rhee &
Coussens, 2002).
Inhibition by TIMPs
Both monomers and multimers of MMP-9 are inhibited by
TIMP-1. The major TIMP-1 binding site of pro-MMP-9 is
located in the hemopexin domain (OConnell et al., 1994).
Another study showed that proMMP-9 multimers have two
high affinity binding sites for TIMP-1 (Olson et al., 2000),
most probably these are also in the hemopexin domain
(OConnell et al., 1994). The hemopexin domain of MMP-9
interacts with the carboxyterminus of TIMP-1 (Goldberg
et al., 1992) and the aminoterminus of both TIMP-1 and
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J. Vandooren et al.
Inhibition by chemicals
Many MMP inhibitory drugs have been developed with the
original idea to use these as peroral treatment for invasive and
metastatic cancers. After the failure of clinical trials of MMP
inhibitors for cancer therapy, we suggested that many of these
drugs may be better candidates for inflammatory and vascular
diseases (Hu et al., 2007; Muroski et al., 2008).
Whereas the search for peptide and peptidomimetic MMP
inhibitors continues, gradually more preclinical studies are
emerging about the usefulness of these inhibitors in inflammation (Hu et al., 2005b, 2006; Dejonckheere et al., 2011;
Qiu et al., 2012a,b).
Although these applications are discussed in forthcoming
sections about the role of MMP-9 in diseases, it is critical to
notice that tetracyclines and chemically modified tetracyclines (CMTs) have been most studied and applied (Paemen
et al., 1996; Sorsa & Golub, 2005). Within this group of
molecules, doxycycline and minocycline, MMP-9 inhibitory
tetracyclines (Paemen et al., 1996) have been most evaluated
(Koistinaho et al., 2005; Xue et al., 2010; Yong et al., 2004;
Zabad et al., 2007). Tetracyclines lower the levels of MMP-9
secretion and also function as inhibitors of MMP-9 activity
(Salo et al., 2006).
Inhibitory chemicals have also been covalently bound to
resins to enable to purify MMPs in their active form. After
activation, MMP-9 is a rather unstable enzyme. With the
use of inhibitor tethered resin, however, active MMP-9 in
biological samples can be purified and detected with such
reagents (Hesek et al., 2006).
Other control mechanisms of gelatinase B activity
As is the case for all enzymes, temperature and pH control
catalytic activity. For MMP-2 and MMP-9 the environmental
pH may differ intracellularly and outside cells. In the
extracellular milieu, which is in equilibrium with body
fluids, the pH is mostly neutral under physiological conditions and this pH corresponds to the optimal one of MMP-9.
However, under conditions of inflammation, the extracellular
pH may decrease considerably and this has consequences for
the activity of MMP-9 and other enzymes. Finally, catalysis
by MMP-9 may also change in patients with fever or
undercooling, when the temperature gradually shifts from
the optimal one at 37 C (Fasciglione et al., 2000).
Complex formation
Homomultimerisation of MMP-9 is an intracellular enzymatic
process: even after prolonged incubation in vitro and in
the presence of glutathione as oxidation-reduction couple,
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Allergy.
autoimmune inflammation. Organ-specific
autoimmune diseases with a presumed role of MMP-9 include
Organ-specific
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DOI: 10.3109/10409238.2013.770819
Dentistry
The role of MMPs in dental pathology is known since long.
Importantly, the use of chemically modified tetracyclines as
treatment of periodontitis is an example of successful drug
development of MMP inhibitors (Sorsa & Golub, 2005). Even
at the interface between normal dentin tissue and artificial
materials, MMPs may play a remodeling role and inhibitors of
MMPs may be useful to prevent disease (De Munck et al.,
2009; Gu et al., 2011).
Muscle disease
Four groups of proteases have been shown to be involved
in skeletal muscle degeneration: the ubiquitin-proteasome
system, lysosomal proteases, calcium-dependent proteases,
and MMPs. However, only the MMPs are directly related to
degradation of the ECM (Liu et al., 2010).
Gelatinase A and B are highly upregulated in a model of
disuse-induced muscle atrophy. But only gelatinase A null
mutant knockout mice show significantly reduced muscle
atrophy as compared to wildtype littermates. With these
findings, the authors (Liu et al., 2010) suggest that
gelatinase A, and not gelatinase B, plays a critical role in
disuse-induced skeletal muscle atrophy. This may be due to
the difference in substrate specificity of both gelatinases.
MMP-2, but not MMP-9, is capable of digesting type I
collagen, which is the dominant type of collagen in the
muscle ECM (Liu et al., 2010).
Tumor necrosis factor-related weak inducer of apoptosis
(TWEAK) (Chicheportiche et al., 1997) was shown to be
involved in muscle atrophy (Dogra et al., 2007) and to induce
MMP-9 by upregulating its promotor through NF-kB and
AP1. In addition, after injecting mice with TWEAK, inflammation, necrosis, basement membrane degradation and
muscle loss were significantly attenuated in MMP-9 KO
mice, proving an important role for TWEAK-induced MMP-9
in myopathy (Li et al., 2009).
Skin conditions
MMP-9 is involved the shedding of desmoglein-3 (dsg-3)
from keratinocytes which can result in alterations of tissue
architecture and the formation of epithelial blisters
(Cirillo et al., 2007). Expression of MMP-9 is induced
in primary skin keratinocytes by IL-13 and MMP-9 and
IL-13 are coexpressed in acute lesions of eczema (Purwar
et al., 2008).
Infrared radiation, present in natural sunlight, causes an
increase in temperature in the human skin. This heat shock
249
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Aneurysms.
Thrombosis.
Transplantation biology
Upon experimental autologous and allogeneic bone marrow
transplantation, recombinant growth factors, such as G-CSF
and chemotactic factors including IL-8, are administered for
repopulation purposes and to mobilize HSCs (vide supra).
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Breast cancer.
Gelatinase B/MMP-9
253
papillomavirus (HPV)-induced cervical cancer, MMP expression analysis with the use of RT-PCR, immunohistochemistry
and gelatin zymography techniques revealed that only MMP-9
expression was significantly upregulated during tumor progression (Giraudo et al., 2004). In this cervical cancer model,
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J. Vandooren et al.
MMP-9 expression was pinpointed to stroma and tumorinfiltrating macrophages (Giraudo et al., 2004). In a clinical
analysis, increased MMP-9 expression levels were correlated
with poor prognosis for the patients (Sheu et al., 2003). In
cervical carcinoma-associated myeloid cells, a STAT3dependent molecular cascade was identified which leads to
MMP-9 induction (Schroer et al., 2011).
Brain tumors.
Prostate cancer.
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Fibrosarcoma.
Eye diseases
MMPs are involved in essentially every physiological process
in the various eye structures (Sivak & Fini, 2002). Increased
levels of both MMP-2 and MMP-9 have been detected in
human choroidal neovascularization (CNV) during agerelated macular degeneration (AMD). In a laser-induced
mouse model for CNV, Mmp2 KO and Mmp9 KO mice had a
lower incidence of CNV and lower disease severity. These
results were also corroborated by overexpression of TIMP-1
and TIMP-2 or injection of MMP inhibitors. The inhibition of
MMP-2, MMP-9 and MT1-MMP may be a promising strategy
for preventing AMD (Lambert et al., 2003).
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yet discovered and the biology was not known. The use of
inhibitors resulted in side-effects, owing to inhibition of closely
related enzymes, such as the ADAMs and ADAMTSs (Apte,
2009; Overall & Lopez-Otin, 2002), lack of specificity, poor
pharmacokinetic studies, toxicity, and the inability to assess
inhibitory efficacy. The roles of MMPs are complex. As we
write, investigations towards tight control of proteolytic
activities are being done (Sela-Passwell et al., 2010).
Selective control of MMP-9 activity may be achieved by
exosite interactions (allosteric inhibitors), by transcriptional
regulation, by reinvestigations of known drugs, with natural
compounds and by highly selective monoclonal antibodies.
MMP-9 can be regulated either by controlling its
transcription and secretion or by direct inhibition of
enzyme activity. Xanthine-derivatives, nonsteroidal antiinflammatory drugs (NSAIDs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are
well known drugs that block MMP-9 transcription and
secretion (Opdenakker et al., 2001b). MMP-9 enzyme activity
can be blocked by compounds such as D-penicillamine,
hydroxamates and tetracyclines which all have a broad range
of inhibition of MMPs (Hu et al., 2007).
REGA-3G12 is an MMP-9 inhibitory antibody which
selectively targets the MMP-9 active site (Martens et al.,
2007). The most recent breakthrough in MMP-specific
monoclonal antibody technology was the development of
the so-called metallobodies. These are engineered antibodies
generated against the Zinc ion coordinated with a tripod
having three histidines and thus mimicking the zinc-binding
site of MMPs. Further immunizations of mice with recombinant MMP will select for highly selective monoclonal
antibodies. This technology was used to generate dualspecific antibodies that were effective in animal models of
inflammatory bowel diseases (Sela-Passwell et al., 2012).
This study is in line with data from other examples of
inflammatory diseases that were successfully treated with
MMP-9 inhibitors, including tetracyclines and many other
compounds (Hu et al., 2007; Qiu et al., 2012a).
The future of MMP-9 inhibition for the treatment of
cancers might lie in finding inhibitors of MMP-9 production
by cancer cells. Such inhibitors have already been found, for
example in prostate cancer (Kong et al., 2007). This goal for
cancer treatment can also be achieved by silencing strategies
for RNAs. MMP-9 siRNA was successfully used in arresting
medulloblastoma tumor growth in an intracranial model.
Silencing of MMP-9 resulted in a cell cycle arrest by ERKmediated p16 expression (Rao et al., 2007).
The use of MMP-9 inhibitors now seems feasible for
neurological disorders and for the treatment of cardiovascular
diseases (Matsumoto et al., 2009). We here address some
additional issues about MMP-9 inhibitors.
Thiol-containing compounds. Thiol-containing compounds
are known for their ability to chelate the active site zinc
(Freskos et al., 1999). The same biochemical principle has
been used with cysteine-containing peptides, that mimick the
peptide sequence of the cysteine switch in the propeptide
(Figure 5) (Hu et al., 2005a,b; Qiu et al., 2012b). Such
cysteine-containing peptides may form the basis to develop
future orally active peptidomimetics.
258
J. Vandooren et al.
Overemphasis has
been placed on the structure and function of MMP-9
monomers. Although further investigations on the monomer
need to continue, the time is ripe to invest also efforts in the
study of the other molecular forms. Are the oligomers dimers
or do these assemble into other multimers? What controls the
subcellular formation, relative abundancy of monomers,
oligomers and heteromers with NGAL? Is the production of
MMP-9 forms cell- or tissue-specific and are these associated
with diseases? Do the oligomers possess similar or differential
functions towards substrates, inhibitors and receptors? Are
these similarly or differentially activated in tissues or body
fluids? Do monomers and multimers have different in vitro
enzyme kinetics, TIMP-1 affinities and inhibition profiles,
receptor binding properties and in vivo pharmacokinetics?
The common idea is to view TIMP-1 as the natural
inhibitor of MMP-9. However, much like MMP-9 itself with
multiple functions associated with individual protein
domains, TIMP-1, with two protein domains, possesses cell
signaling functions in addition to its role as inhibitor. This
implies that high-levels of MMP-9 might also result in a
decrease of free TIMP molecules and therefore a decrease in
TIMP-mediated signaling (Moore & Crocker, 2012). Another
possibility to consider is to target the TIMP-1/MMP-9 binding
interface. Unlike for other MMPs, TIMP-1 is able to bind both
the active site of active MMP-9 and the hemopexin domain.
Therefore, excess levels of proMMP-9 can also result in
TIMP-1 scavenging and have pathological effects.
A popular tool for the study of MMP-9 function is the use of
inhibitors. However, since no specific MMP-9 inhibitors exist,
care should be taken when interpreting results with presently
available inhibitors (Hu et al., 2007). An alternative powerful
tool, however, is the use of Mmp9 knockout mice and WT mice
with an identical genetic background (Whatling et al., 2004).
However, appropriate validation of genetic backgrounds is
indispensable, as has been shown in previous studies (Geurts
et al., 2011). Differences in the genetic backgrounds may be
one of the possible explanations for discrepancies observed
with mouse models of ALS (Dewil et al., 2005; Kiaei et al.,
2007). A further issue about the use of Mmp9 gene knockout
mice is the observation of compensation mechanisms. This
may be avoided with the use of organ- or tissue-specific and
conditional MMP-9 knockout mice.
Gelatinase B/MMP-9
DOI: 10.3109/10409238.2013.770819
259
dystrophy patients includes transplantation of mesoangioblasts (Minasi et al., 2002; Sampaolesi et al., 2003,
2006). For optimal therapy, the transplanted cells need to be
delivered to the skeletal muscles, which is often difficult in
late stage muscular dystrophy due to sclerosis and fat
infiltration into the skeletal muscles. In a recent study, these
problems were overcome by engineering tendon fibroblasts to
produce MMP-9 in combination with the angiogenic factor
PLGF. The engineered fibroblasts were injected into late
stage dystrophic muscles and resulted in restored microcirculation and a reduction in connective tissue deposition. In
addition, subsequent cell therapy was equally efficient as in
early stage dystrophic mice (Gargioli et al., 2008).
Recently, it was
demonstrated that TIMP-1-free MMP-9 from neutrophils is a
potent pro-angiogenic factor (Ardi et al., 2007, 2009). This
260
J. Vandooren et al.
Declaration of interest
This manuscript is submitted to Critical Reviews in
Biochemistry and Molecular Biology exclusively. The authors
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