The MMP family has 28 members that share a common core structure. Typically MMPs consist of a propeptide of about 80 amino acids, a catalytic metalloproteinase domain of about 170 amino acids, a linker peptide [hinge region] of variable lengths and a hemopexin domain of about 200 amino acids [Fig. 1]. The catalytic domain contains the Zn2+ binding motif HEXXHXXGXXH and a conserved methionine, forming a ‘Met-turn’ 8-residues downstream, which supports the active site cleft structure around the catalytic Zn2+ [Bode et al., 1993]. MMP-7, -23 and -26 are exceptions as they lack the linker peptide and the hemopexin domain. MMP-23 has a unique C-terminal cysteine-rich domain and an immunoglobulin-like domain immediately after the C-terminus of the catalytic domain [Ohuchi et al., 1997; Holmbeck et al., 1999; Nagase et al., 2006; Cauwe et al., 2007] [Table 1].
From the evolutionary point of view MMPs have been classified depending on their primary sequence into 6 subgroups [A–F]: subgroup A [MMP-19, -26, -28], B [MMP -11, -21, -23], C [MMP-17, -25], D [MMP-1, -3, -8, -10, -12, -13, -27], E [MMP-14, -15, -16, -24], and F [MMP-2, -7, -9, -20] [Huxley-Jones et al., 2007]. However, MMPs are more commonly classified on the basis of their structure, substrate and subcellular localization into collagenases, gelatinases, stromelysins, matrilysins, membrane-type [MT]-MMPs and others.
Collagenases include MMP-1, -2 [neutrophil collagenase], -13 and -18. These MMPs play an important role in cleaving fibrillar collagen type I, II and III into characteristic 3/4 and 1/4 fragments. They first unwind triple helical collagen then hydrolyze the peptide bonds [Fig. 2]. The MMPs hemopexin domains are essential for cleaving native fibrillar collagen while the catalytic domains are needed for cleaving noncollagen substrates [Chung et al., 2004; Nagase and Fushimi, 2008]. MMP-13 [collagenase 3] is overexpressed in cartilage tissues of osteoarthritis patients and is very efficient in degrading type II collagen [Dalvie et al., 2008].
Gelatinases include gelatinase A [MMP-2] and gelatinase B [MMP-9]. MMP-2 cleaves collagen in two phases, the first resembling that of the interstitial collagenases, followed by gelatinolysis, which is promoted by the fibronectin-like domain [Aimes and Quigley, 1995; Patterson et al., 2001]. The collagenolytic activity of MMP-2 is much weaker than collagenases. However, because proMMP-2 is recruited to the cell surface and activated by the membrane-bound MT-MMPs, it may accumulate pericellularly and express significant local collagenolytic activity [Nagase et al., 2006].
Stromelysins 1, 2 and 3, also known as MMP-3, -10, and -11, respectively, have the same domain arrangement as collagenases, but do not cleave interstitial collagen. MMP-3 and -10 are similar in structure and substrate specificity, while MMP-11 is distantly related. MMP-3 and MMP-10 digest a number of ECM molecules and participate in proMMP activation, but MMP-11 has very weak activity toward ECM molecules. Also, MMP-3 and -10 are secreted from the cells as inactive proMMP, but MMP-11 is activated intracellularly by furin and secreted from the cells as an active enzyme [Pei and Weiss, 1995].
Matrilysins include MMP-7 and -26, which lack the hemopexin domain. MMP-7 acts intracellularly in the intestine to process procryptidins to bactericidal forms. MMP-7 degrades ECM components, and also cleaves cell surface molecules such as Fas–ligand, pro-tumor necrosis factor-α, syndecan 1 and E-cadherin to generate soluble forms [Parks et al., 2004]. MMP-26 is expressed in breast cancer cells [Marchenko et al., 2004].
Membrane-Type MMPs [MT-MMPs] include four transmembrane MMPs, MP-14, -15, -16 and -24, and two glycosyl-phosphatidylinositol-anchored MMPs, MMP-17 and -25 [Ohuchi et al., 1997; Holmbeck et al., 1999] [Table 1]. MT-MMPs have a furin-like pro-protein convertase recognition sequence at the C-terminus of the propeptide. They are activated intracellularly and the active enzymes are expressed on the cell surface. All MT-MMPs except MT4-MMP [MMP-17] can activate proMMP-2 [English et al., 2001]. MT1-MMP [MMP-14] activates proMMP-13 on the cell surface [Knauper et al., 1996].
Other MMPs include MMP-12, -20 and -27 which have a domain arrangement and chromosome location similar to stromelysins. MMP-12 [metalloelastase] is expressed in macrophages and is essential for macrophage migration [Shipley et al., 1996] and is also found in hypertrophic chondrocytes and osteoclasts [Kerkela et al., 2001; Hou et al., 2004]. MMP-19 is a potent basement membrane-degrading enzyme that plays a role in tissue remodeling, wound healing and epithelial cell migration by cleaving laminin5γ2 chain [Stracke et al., 2000; Sadowski et al., 2003a; Sadowski et al., 2003b; Sadowski et al., 2005]. MMP-19 deficient mice develop diet-induced obesity due to adipocyte hypertrophy, but are less susceptible to skin cancers induced by chemical carcinogens [Pendas et al., 2004].
Enamelysin [MMP-20] is a tooth-specific MMP expressed in newly formed tooth enamel and digests amelogenin [Ryu et al., 1999]. Amelogenin imperfecta, a genetic disorder with defective enamel formation involves mutation at MMP-20 cleavage sites [Barron et al., 2001].
MMP-21 is an MMP with measurable gelatinolytic activity expressed in various fetal and adult tissues, macrophages of granulomatous skin lesions, fibroblasts in dermatofibromas, and also in basal and squamous cell carcinomas [Ahokas et al., 2003; Skoog et al., 2006].
MMP-23 is unique among the matrixins as it lacks the cysteine switch motif in the propeptide, and the hemopexin domain is substituted by cysteine-rich immunoglobulin-like domains [Velasco et al., 1999]. MMP-23 is a type II membrane protein regulated by a single proteolytic cleavage for both its activation and secretion [Pei et al., 2000]. It is expressed predominantly in ovary, testis and prostate, suggesting a specialized role in reproduction [Velasco et al., 1999]. MMP-27 is expressed in B-lymphocytes and is overexpressed in cultured human lymphocytes treated with anti-[IgG/IgM] [Bar-Or et al., 2003].
Epilysin [MMP-28] was first cloned from the human keratinocyte and testis cDNA libraries, and is expressed in the lung, placenta, heart, gastrointestinal tract and testis [Lohi et al., 2001; Saarialho-Kere et al., 2002]. MMP-28 is elevated in cartilage from patients with osteoarthritis and rheumatoid arthritis [Kevorkian et al., 2004; Momohara et al., 2004].
MMPs are regulated at multiple levels including transcription, secretion, activation of the zymogen forms, extracellular inhibition and internalization by endocytosis. MMP activity is positively modulated by ions and reagents that induce MMP cleavage and activation. Zn2+ chelators suppress MMP activity by depriving MMPs from the Zn2+ critical for their activity [Newsome et al., 2007]. Cu2+ ions may decrease MMP-2 secretion [Guo et al., 2005]. MMPs are also inhibited by both endogenous and exogenous inhibitors.
Matrixins are synthesized as pre-proenzymes and the signal peptide is removed during translation to generate proMMPs. ProMMPs have a ‘cysteine switch’ motif PRCGXPD in which the cysteine residue coordinates with the catalytic Zn2+ in the catalytic domain, keeping the proMMPs inactive [Van Wart and Birkedal-Hansen, 1990]. Activation of proMMPs involves detaching of the hemopexin domain, which can be accomplished extracellularly by other MMPs or other classes of proteases. For example, MMP-3 activates a number of proMMPs including the processing of proMMP-1 into fully active MMP-1 [Suzuki et al., 1990]. ProMMP-2 is not activated by general proteinases; instead its activation takes place on the cell surface by most MT-MMPs, but not MT4-MMP [Mulvany et al., 1996]. MT1-MMP-mediated activation of proMMP-2 requires TIMP-2 [Butler et al., 1998; Wang et al., 2000]. ProMMP-2 forms a complex with TIMP-2 through their C-terminal domains, thus permitting the N-terminal inhibitory domain of TIMP-2 to bind to MT1-MMP on the cell surface. The cell surface-bound proMMP-2 is then activated by an MT1-MMP that is free of TIMP-2. Alternatively, MT1-MMP inhibited by TIMP-2 can act as a “receptor” of proMMP-2. The MT1-MMP-TIMP-2-proMMP-2 complex is then presented to an adjacent free MT1-MMP for activation [Itoh et al., 2001]. Thus, the TIMP-2 environment may determine the MT1-MMP choice between direct cleavage of its own substrates and activation of MMP-2 [Kudo et al., 2007]. However, for a number of MMPs including membrane-bound MMP-11, -23, -28, activation occurs intracellularly via the endopeptidase furin, which selectively cleaves paired base residues [van de Ven et al., 1990; Pei and Weiss, 1995; Velasco et al., 1999; Marchenko and Strongin, 2001].
Oxidants generated by leukocytes or other cells can both activate [via oxidation of the prodomain thiol followed by autolytic cleavage] and inactivate MMPs [via modification of amino acids critical for catalytic activity], providing a mechanism to control bursts of proteolytic activity. In vitro, a number of proMMPs are activated by reactive oxygen species [ROS] [Okamoto et al., 1997; Fu et al., 2001; Gu et al., 2002; Fu et al., 2004]. Foam cell derived ROS can activate proMMP-2. Nitric oxide [NO] may also activate proMMP-9 during cerebral ischemia by reacting with the thiol group of the cysteine switch and forming an S-nitrosylated derivative [Gu et al., 2002]. Also, hypoxia may increase MMP-2 and -9 mRNA levels [Oh et al., 2008]. Other MMPs such as MMP-9 depend predominantly on plasmin for activation [Ogata et al., 1992]. MMP-7 is activated both by MMP-3 and by hypochlorous acid, a product of myeloperoxidase found in plaque macrophages. MMP-7 can activate MMP-1 [Fu et al., 2001; Dollery and Libby, 2006]. Also, serine proteinases such as neutrophil elastase, may favor matrix breakdown by inactivating TIMPs [Desrochers et al., 1992; Liu et al., 2000].
MMPs can be activated by thiol-modifying agents such as 4-aminophenylmercuric acetate, mercury chloride, and N-ethylmaleimide, oxidized glutathione, sodium dodecyl sulfate, and chaotropic agents by causing disturbance of the cysteine-Zn2+ interaction at the cysteine switch. MMPs can also be activated by heat treatment and low pH [Chen et al., 1993].
TIMPs and α2-Macroglobulin are two major endogenous inhibitors of MMPs. TIMPs bind MMPs in a 1:1 stoichiometry [Fig. 3]. There are 4 TIMPs in humans; TIMP 1–4. TIMP-1 and -3 are glycoproteins, while TIMP-2 and -4 do not contain carbohydrates. TIMPs have an N-terminal domain [125 aa] and C-terminal domain [65 aa]; each containing 3 disulfide bonds. The N-terminal domain folds as a separate unit and is capable of inhibiting MMPs [Williamson et al., 1990; Murphy et al., 1991]. The TIMP molecule wedges into the active-site cleft of MMP in a manner similar to that of the substrate. Cys1 is instrumental in chelating the active site Zn2+ with its N-terminal α-amino group and carbonyl group, thereby expelling the water molecule bound to the catalytic Zn2+ [Fig. 3]. TIMPs inhibit all MMPs tested thus far, but TIMP-1 is a poor inhibitor of MT1-MMP, MT3-MMP, MT5-MMP and MMP-19 [Baker et al., 2002]. TIMPs also inhibit a broader spectrum of metalloproteinases. TIMP-1 inhibits ADAM-10 while TIMP-2 inhibits ADAM12 [Amour, 2000], TIMP-3 has a much broader inhibition profile including ADAM-10, -12 [Jacobsen et al., 2008] and -17 [Amour et al., 2000] and ADAMTS-1, -2, -4 and -5 [Kashiwagi et al., 2001; Rodriguez-Manzaneque et al., 2002]. Because of this broad inhibitory spectrum, TIMP-3 ablation in mice causes lung emphysema-like alveolar damage [Leco et al., 2001] and faster apoptosis of mammary epithelial cells after weaning [Fata et al., 2001], whereas TIMP-1-null mice and TIMP-2-null mice do not exhibit obvious abnormalities.
Endogenous inhibition of MMPs by TIMPs. The TIMP molecule wedges into the active-site cleft of MMP in a manner similar to that of the substrate. Cys1 is instrumental in chelating the active-site Zn2+ with its N-terminal α-amino group and carbonyl group, thereby expelling the water molecule bound to the catalytic Zn2+.
MMP activity is partly regulated by α2-macroglobulin and related proteins. Human α2-macroglobin, a glycoprotein consisting of four identical subunits and found in blood and tissue fluids, acts as a general proteinase inhibitor. Most endopepidases are inhibited by entrapping the enzyme within the macroglobulin. The complex is then rapidly cleared by endocytosis via a low density lipoprotein receptor-related protein-1 [Strickland et al., 1990].
Other proteins inhibit selected members of MMPs: a secreted form of β-amyloid precursor protein inhibits MMP-2 [Higashi and Miyazaki, 2003]; a C terminal fragment of procollagen C-proteinase enhancer protein inhibits MMP-2 [Mott et al., 2000]; tissue factor pathway inhibitor-2, a serine proteinase inhibitor, inhibits MMP-1 and -2 [Herman et al., 2001], and RECK, a GPI-anchored glycoprotein, inhibits MMP-2, -9 and -14. However, the mechanism of action of these inhibitors is not well-described [Murphy and Nagase, 2008].
Several MMP inhibitors [MMPIs] have been developed and some of them have been pursued as investigative or therapeutic tools [Jacobsen et al.],2010] [Table 2]. Because the mechanism by which MMPs cleave their substrates requires catalytic Zn2+ ion, the design of MMPI has traditionally utilized zinc binding globulin [ZBG]. ZBGs in MMPI displace the zinc-bound water molecule and inactivate the enzyme [Rao, 2005]. ZBG also acts as an anchor to lock the MMPI in the active site and direct the backbone of the inhibitor into the target substrate-binding pockets [Table 2] [Jacobsen et al.],2010].
ZBG MMP Inhibitors and their IC50 [μM, unless noted otherwise]
| 1 [Batimastat] | 3 nM | 4 nM | 20 nM | 10 nM | 10 nM | |||||||
| 2 Prinomastat AG3340 | 8.3 nM [Ki] | 0.05 nM | 0.3 nM | 54 nM | 0.26 nM | 0.03 nM | 0.33 nM | O2-induced retinal neovascularization, neuronal hypoxic injury, ventilator-induced lung injury, lung cancer, uveal melanoma, gliomas, prostate cancer | [Price et al., 1999; Shalinsky et al., 1999; Foda et al., 2001; Garcia et al., 2002; Ozerdem et al., 2002; El-Bradey et al., 2004] | |||
| 3 | 9 nM | [Borkakoti et al., 1994] | ||||||||||
| 4 RS-104966 | 23 nM [Ki] | 0.13 nM [Ki] | [Lovejoy et al., 1999] | |||||||||
| 5 | >400 | 0.135 | 0.081 | 1.1 | 0.042 | >7 | 1.8 nM | 5 | Osteoarthritis | [Hu et al., 2005] | ||
| 6 | >6 | 0.351 | >22 | 1.3 | 0.002 | 0.120 | 1.1 | Chronic obstructive pulmonary disease | [Li et al., 2009] | |||
| 7 | 0.147 | 0.09 nM | 0.050 | >1 | 1.6 nM | 6.7 nM | 9.8 nM | Stop tumor invasion | [Rossello et al., 2005] | |||
| 8 | 14 | 0.529 | 0.001 | 2.42 | 20.1 | Chronic non-healing wounds | [Whitlock et al., 2007] | |||||
| 9 | 0.03 | 9.8 nM | 1.7 | 0.475 | 0.003 | 17 | [Ledour et al., 2008] | |||||
| 10 | 3.3 | 0.032 | 0.057 | [Michaelides et al., 2001] | ||||||||
| 11 | >50 | >120 | 80 | >120 | [Michaelides et al., 2001; Campestre et al., 2006] | |||||||
| 12 | 3.4 | [Campestre et al., 2006] | ||||||||||
| 13 | 58 | 200 | [Campestre et al., 2006] | |||||||||
| 14 | 15 | [Onaran et al., 2005] | ||||||||||
| 15 | 270 | [Onaran et al., 2005] | ||||||||||
| 16 | 0.049 [Ki] | 1.1 nM | 0.470 | 0.04 | 0.57 nM | 0.024 | [Hurst et al., 2005] | |||||
| 17 | >100 | 0.005 1.2 | 0.04 >100 | 0.6 nM | [Pochetti et al., 2006] | |||||||
| 18 | 0.160 | 0.02 | 0.150 | 1.4 | 1.1 nM | 0.059 | 0.013 | 0.032 | Acute liver disease, multiple sclerosis, breast cancer | [Van Lint et al., 2005; Biasone et al., 2007; Folgueras et al., 2008] | ||
| 19 | 4.65 [Ki ] | 18.4 | 3.91 | 0.11 | 4.7 | 30.1 | [Matziari et al., 2004] | |||||
| 20 | >100 | 0.02 | 90 | 20 | >100 | Melanoma | [Breuer et al., 2004] | |||||
| 21 | >100 | 4 | >100 | >100 | 20 | >100 | >100 | Melanoma, prostate cancer | [Hoffman et al., 2008] | |||
| 22 | >500 | N/A | 6 [Ki] | N/A | [Cook et al., 2004] | |||||||
| 23 | 16 | 0.01 | 1.8 | 0.015 | 0.012 | 0.01 | Anti-angiogenic and anti-invasive in tumor models | [Grams et al., 2001; Maquoi et al., 2004] | ||||
| 24 | 0.14 | 0.14 | 0.22 | 0.36 nM | Osteoarthritis | [Reiter et al., 2006] | ||||||
| 25 | >50 | >50 | 0.019 | [Puerta et al., 2005] | ||||||||
| 26 | >50 | 0.92 | 0.56 | >50 | 0.086 | 27.1 | 0.018 | 4.1 | Heart ischemia and reperfusion | [Romero-Perez et al., 2008] | ||
| 27 | >1 | 0.005 | 0.056 | 2.4 nM | 2.5 nM | Brain edema following ischemia–reperfusion | [Jadhav et al., 2008] | |||||
| 28 | >50 | 4.4 | 0.077 | >50 | 0.248 | 32.3 | 0.085 | 6.6 | [Romero-Perez et al., 2008] | |||
| 29 | >50 | 16.5 | 41.7 | >50 | 3.8 | >50 | 1.2 | 16.5 | [Romero-Perez et al., 2008] | |||
| 30 | >50 | 9.3 | 0.24 | >50 | 0.064 | >50 | 0.022 | 20.6 | [Romero-Perez et al., 2008] | |||
| 31 | >50 | 7.6 | >50 | >50 | 5.0 | >50 | 6.7 | 6.7 | [Romero-Perez et al., 2008] | |||
| 32 [100 μM] | 21% | 34% | 34% | 33% | [Yan and Cohen, 2007] | |||||||
| 33 [50 μM] | 52% | 23% | 45% | 54% | [Yan and Cohen, 2007] |
Early MMPIs typically included hydroxamic acids [ZBG1], carboxylates [ZBG2], thiols, and phosphonic acids [phosphorus-based ZBGs] [Skiles et al., 2001]. Of these MMPIs, hydroxamic acids were preferred due to their relative ease of synthesis and potent binding [Brown et al., 2004; Elaut et al., 2007; Gupta et al., 2007; Moss et al., 2008]. A contributing factor to the effectiveness of hydroxamates is the hydrogen bonding that results between the heteroatoms of the ZBG and neighboring amino acid residues that are conserved in all MMP active sites. Several hydroxamate- and carboxylate-based MMPIs show good selectivity among different MMPs [Cherney et al., 2004; Rossello et al., 2005; Nakatani et al., 2006; Whitlock et al., 2007; Subramaniam et al., 2008]. Although hydroxamate MMPIs are potent inhibitors, many of them have shown adverse musculoskeletal side effects and poor oral bioavailability [Vihinen et al., 2005; Fingleton, 2008].
Research has been directed toward the development of MMPIs with increased selectivity toward a specific MMP. The development of highly specific synthetic active-site-directed MMPIs necessitates identifying the specific structural features of each individual MMP that can be exploited to obtain the desired selectivity. Site specific delivery is another approach that permits the use of MMPIs with low potency. With this goal in mind, a series of biphenyl sulfonamide carboxylate MMPIs with high selectivity for MMP-13 were designed for treatment of osteoarthritis [Li et al., 2005]. The carboxylic acid scaffold of those MMPIs was also used to develop selective MMP-12 inhibitors for treatment of chronic obstructive pulmonary disease [Churg et al., 2003]. Also, a series of MMPIs with improved selectivity towards MMP-12 over MMP-13 were generated by using a fused ring system. Selective hydroxamic acid inhibitors of MMP-2 have also been developed as potent anti-angiogenic agents. Inhibitor 7 is the most selective MMP-2 inhibitor of this series [Rossello et al., 2005]. Another selective hydroxamate MMPI with specificity towards MMP-3 was designed for treatment of chronic non-healing wounds [Whitlock et al., 2007]. Other ZBGs have been developed to improve selectivity, bioavailability, and pharmacokinetics, and include oxygen, nitrogen, and sulfur donor–atom ligands and monodentate, bidentate, and tridentate chelators.
Hydrazide [ZBG3] and sulfonylhydrazide [ZBG4] analogs of the hydroxamate MMPI illomastat have been developed [Table 2] [Auge et al., 2003]. Sulfonylhydrazide 9 is a potent inhibitor of MMP-1, -2, and -9 with suboptimal potency [Ledour et al., 2008]. Mercaptosulfide [ZBG8] inhibitors target MMP-14. MMPIs with phosphorus-based ZBGs have also demonstrated improved selectivity. Inhibitor 18 is a potent phosphonate inhibitor that exhibits selectivity for MMP-8 [Hurst et al., 2005]. Other phosphorus-based ZBG for MMPI include the carbamoyl phosphonate ZBG [ZBG9] [Jacobsen et al.],2010].
The net negative charge on ZBGs prevents cell penetration and restricts these MMPIs to the extracellular space, and therefore contributes to their low toxicity [Hoffman et al., 2008]. Several MMPIs based on these ZBGs are selective for MMP-2 and have been evaluated in both in vitro and in vivo models of tumor invasion and angiogenesis. Compound 20 shows marked specificity towards MMP-2 with little inhibition of MMP-1, -3, -8, and -9. Administration of compound 20 intraperitoneally at 50 mg/kg/day for three weeks in a murine model of melanoma metastasis results in 55% inhibition of lung metastasis [Breuer et al., 2004].
Compound 21 was introduced as a carbamoyl phosphonate MMPI that targets MMP-2 and -9, but spares MMP-1, -3, -8, -12, and -13. Compound 21 dose-dependently inhibits cell invasion in a Matrigel assay and prevents tumor colonization in the murine melanoma model, and shows efficacy via both the oral and intraperitoneal routes. Compound 21 has shown promising results in reducing tumor growth and metastasis in the more aggressive murine model developed by implantation of human tumor prostate cells in immunodeficient mice. These ZBGs have the advantage of being water soluble at physiological pH and are not acutely toxic at the concentrations used in the murine models [Hoffman et al., 2008].
Nitrogen-based ZBGs [ZBG10–16] have binding preference to late transition metals and improved selectivity towards Zn2+-dependent enzymes [Cook et al., 2004; Jacobsen et al., 2006]. An example of these ZBGs is compound 22, a modest inhibitor of MMP-9 that does not inhibit MMP-1, -2, or -12. The most extensively studied nitrogen-based ZBGs are the pyrimidine-2,4,6-trione and dionethione inhibitors. The pyrimidine-2,4,6-trione group is a known constituent of many FDA-approved drugs such as the barbiturates, and therefore its metabolic disposition and bioavailability have been well-studied [Grams et al., 2001]. The pyrimidine-2,4,6-trione MMPIs were first optimized for gelatinase specificity and as anticancer drugs [Foley et al., 2001].
Compound 23 was evaluated for its anti-invasive, anti-tumorigenic, and anti-angiogenic activity. Compound 23 inhibits chemoinvasion by 85% at concentrations as low as 10 nM and shows anti-cancer efficacy in several in vitro and in vivo models [Maquoi et al., 2004]. Pyrimidine-2,4,6-trione MMPIs have also been optimized to inhibit MMP-13 as part of the development of anti-osteoarthritis drugs [Blagg et al., 2005; Kim et al., 2005; Reiter et al., 2006; Freeman-Cook et al., 2007]. Pyrimidinetrione-based inhibitors have demonstrated up to 100-fold selectivity for MMP-13 over MMP-2, -8, and -12 [Reiter et al., 2006].
A series of heterocyclic bidentate chelators ZBG20–30 was developed as alternative ZBGs and MMPIs [Puerta et al., 2004] . These ZBGs have some features in common with hydroxamic acids but with better biostability and tighter Zn2+ binding due to ligand rigidity and, in some cases, the incorporation of sulfur donor atoms [Puerta and Cohen, 2003; Jacobsen et al., 2007]. In vitro assays showed that these ZBGs inhibited MMP-1, -2, and -3 with greater potency than acetohydroxamic acid [Puerta et al., 2004], and cell viability assays showed that these ZBGs have low toxicity [Puerta et al., 2006]. Several of these ZBGs have been developed into complete MMPIs with good potency [Puerta et al., 2005; Agrawal et al., 2008]. Compound 25 is a pyrone-based inhibitor with greater selectivity toward MMP-3 over MMP-1 and -2 [Puerta et al., 2005]. Compound 26 is an inhibitor of MMP-12 at low concentrations, and a potent inhibitor of MMP-2, -3, and -8, but significantly less effective against MMP-1, -7, -9, and -13 [Agrawal et al., 2008]. In an ex vivo rat heart model of ischemia and reperfusion, hearts treated with 5 μM of compound 26 were found to recover more than 80% of their original contractile function compared with 50% of untreated hearts [Agrawal et al., 2008].
Other ZBGs include 6-, 7-, and 8-membered heterocyclic chelators as 1-hydroxy-2-piperidinone, 1-hydroxyazepan-2-1, 1-hydroxyazocan-2-1, and 1-hydroxy-1,4-diazepan-2-1 [Zhang et al., 2008]. Compound 27, which uses ZBG20, is selective to MMP-1 and moderately selective to MMP-3. Compound 27 exhibits a half-life of 47 h in rats when administered at 2 mg/kg intravenously, and causes reduction in brain edema following ischemia–reperfusion in a mouse model of transient mid-cerebral artery occlusion [Zhang et al., 2008].
Just as changes in the ZBG can generate differences in selectivity, changes in the connectivity and point of attachment of the ZBG to the backbone can also result in dramatic changes in potency and selectivity. For example, compound 30 has an IC50 of 240 nM against MMP-3 [Puerta et al., 2005; Agrawal et al., 2008], whereas the structural isomer compound 32 shows weaker inhibition [~30%] at concentrations as high as 100 μM [Yan and Cohen, 2007]. This comparison shows that two MMPIs with similar chemical formula, ZBG and backbone, may have vastly different activities due to the relative positioning of the backbone on the ZBG.
MMPIs that do not have a ZBG and hence do not bind the catalytic Zn2+ ion have been developed [Table 3] [Jacobsen et al.; Morales et al., 2004; Dublanchet et al., 2005; Engel et al., 2005; Gooljarsingh et al., 2008; Li et al., 2008; Pochetti et al., 2009]. The rationale for this strategy is that eliminating or minimizing the interaction with the catalytic Zn2+ ion best achieves MMP selectivity, because the metal site is the most conserved feature in all MMPs. Nearly all Non-zinc-binding MMPIs show high MMP-13 selectivity and effectiveness in the treatment of osteoarthritis in animal models [Johnson et al., 2007; Li et al., 2008].
Non-ZBG and Mechanism-Based MMP Inhibitors and their IC50 [μM, unless noted otherwise]
| Non-ZBG MMP Inhibitors | |||||||||||
| 34 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | 0.03 | >100 | Osteoarthritis | [Johnson et al., 2007] |
| 35 | >100 | 0.39 | 1.7 | 0.98 | 1.4 | 0.014 | 0.27 | [Morales et al., 2004] | |||
| 36 | >100 | 6.6 | 5.1 | >100 | 24 | 4.9 | [Morales et al., 2004] | ||||
| 37 | >30 | >30 | >30 | >30 | >100 | >100 | >100 | 0.00067 | >30 | Osteoarthritis | [Johnson et al., 2007] |
| 38 | 6.6 | [Engel et al., 2005] | |||||||||
| 39 | 0.072 | [Engel et al., 2005] | |||||||||
| Mechanism-Based MMP Inhibitors | |||||||||||
| 40 | 73 | 0.028 | 4 | 67 | 0.400 | 0.110 | Inhibits bone metastasis in prostate cancer, liver metastasis in T-cell lymphoma | [Kruger et al., 2005; Bonfil et al., 2006; Bonfil et al., 2007; Lee et al., 2007] | |||
| 41 | 25 | 186 | [Bernardo et al., 2002] | ||||||||
| 42 | 0.046 | 10 | 0.100 | 0.21 | [Bernardo et al., 2002] | ||||||
| 43 | 128 | 0.006 | 2.2 | 31 | 0.16 | 0.09 | [Lee et al., 2007] | ||||
| 44 | [Lee et al., 2007] | ||||||||||
| 45 | 140 | 0.023 | 0.600 | 18.2 | 0.005 | 0.145 | [Lee et al., 2009a] |
Several non-zinc-binding MMPIs show a noncompetitive mechanism of inhibition [Gooljarsingh et al., 2008] . Compound 37 inhibits MMP-13 but does not appreciably inhibit MMP-1, -2, -3, -7, -8, -9, -12, -13, -14, or -17. Binding of these inhibitors may rigidify the enzyme active site into a specific conformation that is less conducive for substrate binding. The flexibility of MMP-13, relative to other MMPs, may allow for this favorable conformation that is not accessible in other MMPs [Engel et al., 2005; Johnson et al., 2007].
As most of these non-zinc-binding MMPIs are potent and selective, derivatives aimed to improve their solubility and drug properties [Li et al., 2008]. The hydrophobicity of these inhibitors is critical in maintaining significant protein–inhibitor interaction that result in high potency, but also results in poor water solubility. To improve the solubility with minimal effect on potency, derivatives were explored to specifically modify the solvent-exposed portions of the molecule while maintaining hydrophobic core structures [Dublanchet et al., 2005].
Preclinical studies with compound 37 have shown encouraging results in models of osteoarthritis. Compound 37 has an efficacy at doses as low as 0.1 mg/kg in MMP-13-induced rat model of cartilage knee joint damage. Also, oral administration of compound 37 twice daily at 30mg/kg resulted in a 68% reduction in the cartilage lesion area of tibial plateaus in rats with surgically induced cartilage knee damage. When the rat joints were subsequently examined for evidence of fibroplasias and expanded inner synovial lining, which are indicative of musculoskeletal syndrome, fibroplasias were absent in rats treated with compound 37, but present in rats treated with broad-spectrum MMPIs. MMPIs of this high degree of selectivity may minimize the toxic side effects associated with broad-spectrum MMPIs. However, it is not clear whether the selectivity of these inhibitors is due to their non-ZBG properties or other factor[s] [Engel et al., 2005; Johnson et al., 2007].
SB-3CT was introduced as the first mechanism-based inhibitor of MMPs. SB-3CT binds in the active site and forms a covalent bond with the substrate protein upon activation by Zn2+ coordination [Table 3] [Jacobsen et al.],2010]. The formation of the covalent bond impedes inhibitor dissociation as compared to the traditional chelating competitive inhibitors. This reduces the rate of catalytic turnover, and decreases the amount of MMPI needed to saturate the enzyme active sites. Compound 40 is a selective inhibitor of MMP-2 and -9 that showed promise in pre-clinical studies as an inhibitor of bone metastasis in prostate cancer and in the prevention of damage caused by cerebral ischemia. The structure of 40 is relatively simple, as reflected by its low molecular weight. The mechanism of inhibition of 40 is similar to that of a “suicide substrate” in which a functional group is activated, leading to covalent modification of the enzyme active site [Bernardo et al., 2002]. Compound 40 exhibits slow-binding kinetics with MMP-2, -3, and -9, with a time scale for establishing equilibrium between the enzyme and inhibitor and the enzyme–inhibitor complex in the order of seconds to minutes. Slow-binding inhibition is characterized by slow dissociation rates, though the binding rate can vary in speed [Morrison and Walsh, 1988]. Progress curves, which display the enzyme activity of MMP-2, -9, and -3 with compound 40 over time, are non-linear [Bernardo et al., 2002]. The curves show that the initial enzyme rate is not maintained and is instead reduced to a new “steady-state rate” of MMP activity. This indicates a slow-binding mechanism of inhibition, characteristic of an interaction between an enzyme and an inhibitor that resists dissociation. The binding of compound 40 with MMPs is nearly irreversible. Following 95% inhibition, MMP-2 regains 50% activity only after 3 days with dialysis, indicating some reversibility and distinguishing it from a true suicide inhibitor, which operates strictly by an irreversible mechanism [Morrison and Walsh, 1988; Bernardo et al., 2002]. The selectivity of compound 40 stems from the difference in the binding kinetics for various MMPs. As demonstrated by the non-linear progress curves, inhibition increases over time, as slow-binding inhibitors do not dissociate readily from the active site [Lee et al., 2005]. The selectivity of compound 40 might be related to its inhibition of MMP-2 and -9 via a slow-binding mechanism while inhibition of MMP-14 occurs through competitive inhibition [Toth et al., 2000].
In preclinical studies, compound 40 has produced anti-cancer effects in both a T-cell lymphoma model and a prostate cancer model [Kruger et al., 2005; Bonfil et al., 2006; Bonfil et al., 2007]. Also, in vitro Matrigel tests showed that 1 μM of compound 40 reduces the invasion ability of human prostate cancer cells by 30% as compared to the vehicle control [Bonfil et al., 2006]. In a mouse model of T-cell lymphoma, compound 40 administered at 5–50 mg/kg/d promotes a dose-dependent reduction in the number of liver metastases [Banke et al., 2005]. At 50 mg/kg/d, compound 40 inhibits liver metastases by 73% and reduces the colony size of the metastases, while the broad-spectrum inhibitor Batimastat has led to increased metastasis in the same tumor model. Additionally, in vitro tests show that 40 does not affect cell growth or viability up to 12.5 μM. Compound 40 also showed promising results in a bone metastasis model of prostate cancer demonstrating reduced tumor growth and angiogenesis [Bonfil et al., 2006]. Also, compound 40 provides neuronal protection in a murine stroke model [Gu et al., 2005]. In mice treated with compound 40 either prior to or 2 h following ischemia induced by right middle cerebral artery occlusion, the infarct volume is decreased to 30% of the control. Administration of compound 40 is protective up to 6 h after the ischemic event in mice. Also, neurological behavioral scores evaluated 24 h after reperfusion show that compound 40-treated mice exhibit significant improvement as compared to the control mice, and the improvement is correlated with the observed infarct volume.
Although compound 40 has significant in vivo activity, it undergoes rapid metabolism in mice [Lee et al., 2007]. This leads to low systemic exposure and suggests that a metabolite of the parent compound may be responsible for the in vivo activity [Celenza et al., 2008]. Compound 43 is a more potent inhibitor of MMP-2, -3, -7, -9, and -14 than compound 40. Also, compound 43 demonstrates slow-binding kinetics with MMP-2, -9, and -14 [Lee et al., 2009a]. Analysis of the different MMPI metabolites led to the design of derivatives that have better in vivo stability and provide longer systemic effects [Lee et al., 2009a]. Compound 45 is a slow-binding inhibitor of MMP-2 and -9, but a competitive inhibitor of other MMPs. Interestingly, the 45 inhibitor is more potent for MMP-9 than MMP-2. The metabolites of 45 are 75% more stable than those of 40, resulting in significantly longer systemic effects.
SB-3CT and its successors show great clinical promise, and the use of mechanism-based, slow-binding inhibitors may provide a new approach to gain selectivity in MMPI design. Other types of covalent modification in the active site may lead to new patterns of selectivity [Jacobsen et al.] 2010]. However, even with the marked improvements in the design of MMPIs, therapeutic inhibition of MMPs is challenging as evidenced by the fact that the antibiotic doxycycline remains the only FDA-approved MMPI [Vihinen et al., 2005; Nuti et al., 2007; Fingleton, 2008; Georgiadis and Yiotakis, 2008]. One limitation of many MMPIs is that their use triggers dose-limiting musculoskeletal syndrome as a side effect, characterized by joint stiffness, pain, inflammation, and tendinitis [Jacobsen et al.; Coussens et al., 2002; Renkiewicz et al., 2003; Fingleton, 2008].
MMPs play a role in many biological processes including tissue remodeling and growth and may also be involved in the tissues defense mechanisms and immune responses. Increased expression of MMPs has been documented during different stages of mammalian development, from embryonic implantation [Harvey et al., 1995] to the morphogenesis of different tissues including lung, bone and mammary gland [Vu and Werb, 2000; Page-McCaw et al., 2007]. Other physiological processes such as growth and wound healing also involve increased expression of MMPs [Ravanti and Kahari, 2000].
MMPs are either secreted from the cell or anchored to the plasma membrane with heparin sulfate glycosaminoglycans. The collagenases MMP-1, -8, -13, and -14 efficiently degrade fibrillar collagens type I, II and III in their triple-helical domains [Lovejoy et al., 1999] [Fig. 2]. Cleavage by these MMPs renders the collagen molecules thermally unstable so that they unwind to form gelatin, which is then degraded by other members of the MMP family including the major gelatinases MMP-2 and -9. MMP-2 localize at the cell surface by binding via its carboxyl terminus to integrin αvβ3 or the MMP-14-TIMP-2 complex [Park et al., 2000]. When bound, the catalytic site of MMP-2 is exposed and can then be cleaved and activated. The α2 chains of collagen IV bind MMP-9 with a high affinity even when MMP-9 is inactive [Olson et al., 1998]. This juxtaposition of enzyme and substrate makes a pool of the enzyme that is rapidly available upon activation for any remodeling events.
The ECM binds growth factors either directly or via growth-factor-binding proteins. Several MMPs stimulate the release of growth factors such as transforming growth factor β [TGF-β], fibroblast growth factor 1 [FGF-1], insulin-like growth factor 1 [IGF-1], TNFα, and heparin-binding epidermal growth factor [HB-EGF] by cleaving either the growth-factor binding protein or the matrix molecule to which these proteins attach. MMP-3 and -7 can cleave the adherens-junction protein E-cadherin [Imai et al., 1997; Manes et al., 1997; Suzuki et al., 1997; Noe et al., 2001; Steinhusen et al., 2001]. MMP-3 can release a soluble form of the adhesion molecule L-selectin from leukocytes, and also sheds membrane-bound HB-EGF to exert signaling functions [Suzuki et al., 1997]. MMP-7 releases soluble Fas ligand which induces apoptosis [Asamoto et al., 2001].
Some growth factors are proteolytically inactivated by MMPs, including the chemokine connective tissue activating peptide III [CTAP-III], monocyte chemoattractant protein and stromal cell-derived factor 1 [McQuibban et al., 2001; Fujiwara et al., 2002]. Growth factors and cytokines are also negatively regulated when MMPs cause shedding of their receptors from the cell membrane, as in the case of surface FGF receptor 1 [Levi et al., 1996].
MMPs also affect the immune system. Defensins are a family of polar antimicrobial peptides that contribute to the innate immune system of some animals. Defensins are synthesized in an inactive form and are activated by the proteolytic removal of the pro-domain by MMP-7, which allows them to insert into the bacterial membrane and disrupt its integrity [Ganz, 1999; Wilson et al., 1999]. MMP-3 and -7 can also cleave all IgG proteins, an important process that prevents the initiation of the complement cascade and helps in the removal of IgG from damaged or inflamed tissue [Gearing et al., 2002]. Also, the receptor of the complement component C1q [C1qR] exists in both a membrane-bound form and a soluble form that inhibits the hemolytic activity of C1q. MT1-MMP releases the membrane bound C1qR, thus allows tumor cells to avoid targeted destruction by the complement system and thereby facilitates tumor-cell survival [Ruiz et al., 1999; Feng et al., 2002; Rozanov et al., 2002].
In addition to their known effects on ECM, experiments have demonstrated diverse effects of MMPs and TIMPs on ECs and VSMCs.
MMPs exert diverse effects on ECs. MMPs affect different receptors and pathways such that the overall effects of MMPs vary depending on the predominant receptors or pathways in the tissue examined. Also, individual MMPs vary in their proteolytic activity and tissue substrates, further contributing to the discrepancy in the effects of MMPs in different studies.
MMPs may regulate EC integrity and vascular permeability. MMP-1 mediates the activation of HUVECs into prothrombotic, proinflammatory, and cell-adhesive state by supernatants from cultured melanoma and colon cancer cells [Goerge et al., 2006]. In mouse aorta, MMP-13 mediates the endothelial protective effect of NO by cleaving the pro-inflammatory intercellular adhesion molecule-1 [ICAM-1] [Tarin et al., 2009]. MMPs may also increase vascular permeability and cause vascular disruption. Upregulation of MMP-2 and -9 mediate the increase in membrane permeability and vascular disruption induced by human immunodeficiency virus-1 envelope gp120 in rat brain [Louboutin et al.],2010]. Also, upregulation of MMP-2 and -9 decreases the integrity of the porcine blood brain barrier [Thanabalasundaram et al.],2010]. In support of these findings, MMPIs such as GM6001 prevent degradation of the tight junction protein occludin and reduce the intercellular gap formation and permeability in porcine cerebral microcapillary ECs [Lischper et al.],2010].
MMPs may have endothelium-dependent vasorelaxant effects. Upregulation of MMP-2 may mediate the bacterial LPS-induced vascular hyporeactivity to vasoconstrictors in rat aorta via an endothelium-dependent mechanism [Cena et al., 2008]. Other studies demonstrated that upregulation of MMPs may be associated with impaired vasorelaxation. Upregulation of MMP-3 and downregulation of TIMP-1 mediate the impaired endothelium-dependent vasodilation, EC apoptosis and endothelial disruption exerted by FOXO3 in HUVECs [Lee et al., 2008]. Also, upregulation of MMP-2 and -9 may be responsible for nicotine-induced endothelial disruption and unresponsiveness of blood vessels to the vasorelaxant acetylcholine, and the MMPI doxycycline partially reversed this effect [Jacob-Ferreira et al.],2010]. In renovascular rat model of hypertension [HTN], antioxidant treatment inhibited the decrease of endothelium-dependent vasorelaxation and attenuated the vascular dysfunction and remodeling by inhibiting oxidative stress-induced upregulation of MMP-2 [Castro et al., 2009]. Further investigations are needed to determine the MMPs targets in ECs and explain their diverse effects in different tissues.
Some studies suggested that MMPs, via PI3K and ATP synthesis, may transactivate EGFR and mediate the α-adrenergic receptor-induced maintenance of vascular tone. Inhibition of the expression of MMP-2 or -7 blunted the phosphorylation of Akt by PI3K and thus inhibited the response to phenylephrine [Phe] in rat mesenteric artery [Nagareddy et al., 2009]. Other studies have shown that Phe-induced contraction of rat aorta is inhibited by MMP-2 [~50%] and MMP-9 [~70%] [Chew et al., 2004]. The MMP-induced inhibition of aortic contraction is concentration- and time-dependent, and is reversible suggesting that the actions of MMPs are not solely due to irreversible degradation of ECM. Also, the inhibitory effects of MMPs on VSM contraction are not likely due to degradation of Phe or the α-adrenergic receptors because MMPs also inhibit prostaglandin F2α-induced contraction, suggesting that the effects of MMPs are not specific to a particular agonist/receptor, but likely involve direct effects on common VSM contraction pathway[s] downstream from receptor activation.
VSM contraction is triggered by increases in Ca2+ release from the intracellular stores and Ca2+ entry from the extracellular space. MMPs do not inhibit Phe-induced contraction in Ca2+-free solution, suggesting that they do not inhibit the Ca2+ release mechanism. On the other hand, MMPs inhibit Phe-induced Ca2+ influx [Chew et al., 2004]. The mechanism by which MMPs inhibit Ca2+ entry could involve direct effects on the Ca2+ channels. MMPs may also affect K+ channels. MMP-2 causes relaxation of rat inferior vena cava [IVC] that is abolished by blockers of the large conductance Ca2+-activated K+ channels such as iberiotoxin, suggesting a role of VSM hyperpolarization [Raffetto et al., 2007]. MMPs also induce collagen degradation and produce Arg-Gly-Asp [RGD]-containing peptides, which could bind to αvβ3 integrin receptors and inhibit Ca2+ entry into VSM [Waitkus-Edwards et al., 2002]. MMPs may also stimulate protease-activated receptors [PARs] and activate signaling pathways that could lead to blockade of VSM Ca2+ channels [Macfarlane et al., 2001]. This is supported by reports that proteases such as thrombin activate PARs and promote endothelium-dependent VSM relaxation by inhibiting Ca2+ influx [Hamilton et al., 1998]. Thus while MMPs may affe ct VSM contraction and ion channels, further studies are needed to define the role of integrins and PARs as possible molecular mechanisms via which MMPs could inhibit VSM contraction.
Evidence suggests that MMPs play a role in VSMC migration. In rat aortic smooth muscle cells [RASMCs] in culture using collagen I gel to mimic ECM, exposure to interstitial flow enhanced cell motility. Upregulation of MMP-1 enhanced flow-enhanced motility, while the MMPI GM-6001 attenuated flow-induced migration. ERK1/2 phosphorylation and increased expression of AP-1 transcription factors c-Jun and c-Fos appear to be involved in MMP-mediated enhancement of flow-induced cell motility [Shi et al.],2010]. Young HASMCs produce active MMP-2 and possess a higher migratory capability than aged cells. The activation of pro-MMP-2 in young cells is likely related to an increase in MT1-MMP content. In contrast, aged cells produce only the inactive zymogen form of MMP-2, and upregulation of TIMPs in aged cells could prevent pro-MMP-2 activation. Interestingly, treatment of young cells with TIMP-1 and -2 promotes aged HASMCs migratory behavior [Vigetti et al., 2008]. MMP-2 activity could also influence chemokine-induced chemotaxis of human VSMC monolayers [Haque et al., 2004]. Also, in vivo knockout of MMP-2 decreases VSMC migration and intima formation in the mouse carotid ligation model [Cheng et al., 2004; Johnson and Galis, 2004] [Table 4].
Vascular Effects of Specific MMP or TIMP Gene Ablation in Mice
| MMP-2 | Reduction of neointima formation in vascular injury. Protection from cardiac rupture post-myocardial Infarction. | [Johnson and Galis, 2004; Matsumura et al., 2005] |
| MMP-9 | Reduction of neointima formation in vascular injury. Protection from cardiac rupture post-MI, vessel stiffness and increased pulse pressure. | [Ducharme et al., 2000; Johnson and Galis, 2004; Flamant et al., 2007] |
| MMP-11 | Accelerated neointima formation in vascular injury | [Lijnen et al., 1999] |
| MMP-14 | Defective angiogenesis | [Holmbeck et al., 1999; Zhou et al., 2000] |
| TIMP-1 | Accelerated neointima formation in vascular injury. Spontaneous cardiac dilatation, augmented dysfunction post-MI. | [Creemers et al., 2003] |
| TIMP-3 | Spontaneous dilated cardiomyopathy | [Fedak et al., 2004] |
Studies have also suggested a role of MMP-9 in VSMC migration. Tanshinone IIA, a major constituent of Salvia miltiorrhiza bunge, inhibits TNF-α-induced HASMC migration, partly through inhibition of MMP-9 activity. Tanshinone IIA also inhibits TNF-α-induced ERK and c-jun phosphorylation, and NF-κB and AP-1 DNA-binding [Jin et al., 2008]. Suppression of MMP-9 expression by down-regulation of NF-κB also mediates the inhibitory effect of curcumin on migration of HASMCs [Yu and Lin],2010]. Also, knockout of MMP-9 is associated with reduced VSMC migration and intima formation observed after filament loop injury [Cho and Reidy, 2002] or carotid arterial occlusion in mice [Galis et al., 2002] [Table 4].
Disruption of the basement membrane is essential for VSMC migration [Aguilera et al., 2003]. MMPs, by degrading the basement membrane, can facilitate a host of ECM integrin interactions leading to activation of focal adhesion kinases [FAK] and increased cell migration. MMPs also cause fragmentation of membrane components such as type I collagen, thus creating new integrin-binding sites. Growth factor receptors, cadherins and integrins mediate signaling pathways that play a role in reorganizing the cytoskeleton in preparation for migration [Carragher and Frame, 2004; Nelson and Nusse, 2004]. MMPs cleave E-cadherin in epithelial cells, VE-cadherin in ECs and N-cadherin in VSMCs [Savani et al., 1995; Uglow et al., 2003], which in turn dissolve adherence junctions and frees the cells to move.
MMPs not only facilitate migration by promoting proteolysis of ECM, but may also directly enhance cell migration. MMP-1 promotes growth and invasion of cells by binding to and cleavage of PAR-1 which reveals a tethered ligand that initiates signaling via a G protein-coupled receptor and activates migration [Boire et al., 2005]. This mechanism allows the cells to sense a proteolytic environment and actively move towards an area of degraded matrix.
MMPIs have been useful in demonstrating the effect of MMPs on VSMC migration. Gene transfer of TIMPs reduces VSMC migration in vitro and inhibits or delays intima thickening in vivo. TIMPs 1–4 delivered directly or by gene transfer inhibit migration of SMCs in vitro [Forough et al., 1996; Baker et al., 1998] and reduce neointima formation in organ cultures of human saphenous vein [George et al., 2000]. TIMP gene transfer also preserves medial basement membrane and inhibits VSMC migration to the intima. Synthetic MMPIs inhibit migration of VSMC from baboon arterial explant cultures [Kenagy et al., 1996], and early VSMC migration in the rat carotid balloon injury model [Islam et al., 2003]. Collectively, experimental evidence supports that MMPs enhance VSMC migration via both extracellular and intracellular effects, and MMPIs could reverse or prevent cell migration.
VSMC proliferation at sites of endothelial injury and lipid deposition plays a role in atheroma formation. In addition to facilitating VSMC migration, MMPs may regulate VSMC proliferation. Pretreatment of human aortic VSMCs with ethanol extract of buddleja officinalis attenuates high-glucose-induced cell proliferation by suppressing MMP-9 activity [Lee et al.],2010]. On the other hand, MMP-9 knockout is associated with inhibition of VSMC proliferation after filament loop injury [Cho and Reidy, 2002], but not after tying off the mouse carotid artery [Galis et al., 2002]. A possible explanation for these inconsistent results is the compensatory activation of other proteases [Newby, 2005].
Several mechanisms have been postulated to explain the regulation of VSMC proliferation by MMPs. MMPs could promote permissive interactions between VSMC and components of the ECM. Integrin-mediated pathways may be essential for stimulation of VSMC proliferation [Morla and Mogford, 2000; Walker et al., 2003]. MMPs may free growth factors from attachment to ECM components or cell surface so that they can act on their receptors. Heparin-binding growth factors, in particular FGF-1 and FGF-2, are potent mitogens for VSMCs and are released by the action of MMPs on proteoglycan core proteins [Visse and Nagase, 2003]. Although ADAMs are often implicated, MMPs could also be responsible for releasing cell surface heparin-bound epidermal growth factor [HB-EGF], which stimulates VSMC proliferation [Hollenbeck et al., 2004; Lucchesi et al., 2004]. MMPs also activate TGF-h by cleaving off the latency-associated peptide [Annes et al., 2003]. MMPs can also liberate active insulin like growth factor 1 [IGF-1] by degrading its binding proteins. Together with signals from FAK, these processes upregulate and/or stabilize key regulators of the cell cycle. Also, MMP-induced cadherin shedding promotes dissolution of adherens junctions and translocation of h-catenin to the nucleus where it acts as a transcription factor to further promote cell proliferation [Uglow et al., 2003; Nelson and Nusse, 2004].
MMPIs have been used to study the role of MMPs in VSMC proliferation. Earlier studies have shown excess neointima proliferation in rat carotid arteries subjected to balloon injury after treatment with the MMPI GM-6001 [Bendeck et al., 1996; Zempo et al., 1996]. However, recent studies demonstrated that synthetic MMPIs inhibit VSMC proliferation in vitro [Lovdahl et al., 2000; Uglow et al., 2003]. Also, inhibition of MMPs is associated with decreased N-cadherin shedding, increased cell membrane N-cadherin levels, decreased h-catenin nuclear translocation and eventually decreased proliferation of cultured human VSMCs. Dismantling of cadherin:catenin complex also occurs in balloon-injured rat carotid arteries in vivo leading to increased expression of the cell cycle gene cyclin D1 which stimulates VSMC proliferation [Slater et al., 2004]. Tetracycline-based MMPIs also reduce VSMC migration and neointima formation after balloon injury of rat carotid artery [Bendeck et al., 2002; Islam et al., 2003]. Collectively, most of the experimental evidence points to a stimulatory effect of MMPs on VSMC proliferation, and inhibition of this effect by MMPIs.
Apoptosis is a form of cell death that involves activation of the intracellular cysteine proteases, caspases. Apoptosis of VSMCs plays a role in attenuating intimal thickening and destabilizing atherosclerotic plaques [Geng and Libby, 2002; Stoneman and Bennett, 2004]. Several factors promote apoptosis including death signals originating from outside the cell and processes within the cell such as DNA damage, cell cycle status and levels of the tumor suppressor p53 [Stoneman and Bennett, 2004]. MMP-7 is involved in the cleavage of N-cadherin and thus modulates VSMC apoptosis. In contrast, survival signals maintain VSMC viability even in the face of a pro-apoptotic environment. Survival pathways are closely linked to those triggering proliferation and therefore could be influenced by MMPs. Survival factors such as PDGF, HB-EGF and IGF-1 act via tyrosine kinase receptors to stimulate the PI3-K/Akt pathway. MMP-2, -7 and -9 cleave cell surface pro-HB-EGF and liberate the soluble active growth factor which binds to EGFR and promotes growth [Hao et al., 2004; Lucchesi et al., 2004]. Activation of PDGFR-β and ERK1/2 is involved in the production of MMP-1 in oxLDL-and 4-hydroxynonenal [4-HNE]-stimulated human coronary VSMCs [Akiba, Kumazawa, 2006]. MMP-1, -2, -8 and -9 degrade members of the IGF binding protein family and thereby increase the bioavailability of IGF-1 and its anti-apoptotic effects [Visse and Nagase, 2003].
Cell–matrix contacts promote VSMC survival, and their disruption leads to apoptosis in a process originally termed anoikis [Frisch and Screaton, 2001]. FAK activation triggered by ECM–integrin interactions induces p53, a survival signaling pathway [Ilic et al., 1998; Almeida et al., 2000]. Regulated MMP production appears to favor FAK activation and hence survival signaling. Conversely, excessive production of MMPs could degrade ECM proteins or integrins and promote anoikis [Levkau et al., 2002]. MMPs may also modulate apoptosis by cleaving death ligands such as TNF-α and Fas ligand and their receptors. MMP-1, -2, - 9, -8 and -13 and the MT-MMPs MMPs 14–17 can cleave pro-TNF-α [Somerville et al., 2003; Visse and Nagase, 2003]. Similarly, MMP-7 sheds Fas-L from the surface of several cell types [Bond et al., 2000; Mannello et al., 2005]. Caspase-mediated cleavage of the DNA repair enzyme poly-ADP ribosepolymerase is an important step in apoptosis, and in isolated cardiac myocytes, nuclear-localized MMP-2 can carry out this cleavage [Kwan et al., 2004].
TIMP-3, but not TIMP-1 and -2, is an effective stimulator of apoptosis in many cells including VSMCs [Baker et al., 1998; Bond et al., 2000], suggesting that an ADAM rather than an MMP is the target. TIMP-4 also stimulates VSMC apoptosis [Guo et al., 2004]. Thus, MMPs appear to regulate VSMC apoptosis via several pathways, and MMPIs could oppose the effects of MMPs on apoptosis.
Atherosclerosis is a multifactorial vascular disease. Dysfunctional endothelium recruits different inflammatory pathways leading to intimal differentiation, VSMC proliferation, ox-LDL deposition, platelet activation and aggregation, and resulting in formation of an atheroma of fat, collagen and elastin with a thin fibrous cap. Dysregulated ECM metabolism may contribute to vascular remodeling during the development and complications of atherosclerotic lesions. Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to facilitate atherogenesis, platelet aggregation and plaque destabilization [Beaudeux et al., 2004; Kadoglou et al., 2005]. MMP-1, -2, -3, -7, -9 and -12 are produced by SMC and macrophages in the arterial wall, and have their highest expression in atherosclerotic lesions [Uzui et al., 2002; Johnson, 2007]. Also, the plaques’ shoulders and regions of foam cell accumulation display increased expression of MMP-1, -9 and stromelysin. Plaque extracts contain activated forms of gelatinases, and gelatinolytic and caseinolytic activities are detected in atherosclerotic areas, but not in uninvolved arterial tissues [Galis et al., 1994]. Importantly, low-fat diet is associated with reduced plaque proteolysis and decline in MMP-1 levels and macrophage content [Aikawa et al., 1998]. Patients on haemodialysis treatment develop atherosclerosis rapidly and show evidence of disordered fibrinolysis/proteolysis balance in their plasma, and MMP-2 may play a role in the development of atherosclerosis in these patients [Pawlak et al., 2008]. Also, urine MMP-9 and TIMP-1 levels are elevated in patients with CAD and acute coronary syndrome [ACS] compared with healthy volunteers [Fitzsimmons et al., 2007]. Plasma levels of MMP-1, -3, and -7 are higher among patients with high intima-media thickness compared with those with low intima-media thickness. MMP-7 is positively associated with carotid calcification [Gaubatz et al.]2010], and an association between plasma levels of MMP-8 with occurrence of carotid plaques has been reported [Djuric et al.]2010]. MMP-10 is induced by C-reactive protein in ECs, and is overexpressed in atherosclerotic lesions. Also, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and atherosclerotic plaques [Rodriguez et al., 2008].
Certain genetic variants of MMPs have shown association with the progression and complications of atherosclerosis. In a 3-year atherosclerosis regression study, the 6A active variant of the MMP-3 promoter was found to correlate with progression of luminal narrowing [Ye et al., 1995] and acute MI [Terashima et al., 1999]. In a study on 139 CAD patients and 119 healthy subjects, MMP-3 5A/6A genetic variant was associated with CAD, and the PON1 variant was associated with the number of diseased coronary vessels [Ozkok et al., 2008]. In a subgroup of the Etude Cas-Temoin de l’Infarctus du Myocarde [ECTIM] study of acute MI, the more active T allele of an MMP-9 functional promoter polymorphism [C1562T] was more common in patients with 3-coronary vessel disease, but did not predict MI [Du et al., 1999]. In a study of 1127 patients, higher MMP-9 serum levels were associated with the T allele, but did not predict cardiovascular death [Blankenberg et al., 2003]. Another study showed associations of MMP-9 genotypes with different stages of carotid atherosclerosis [Rauch et al., 2008]. Animal studies also showed an association between MMP levels and atherosclerosis. MMP-9 deficiency reduced atherosclerotic lesion size in ApoE−/− mice [Luttun et al., 2004], and in the carotid ligation mpdel, hypercholesterolaemic MMP-9−/− mice showed a reduced plaque burden as compared to wild-type mice [Choi et al., 2005].
MMPs contribute to the pathophysiology of atherosclerosis by interacting with several pathways that regulate the process. Vascular inflammation, an important factor in the atherogenic process, promotes the production of MMPs. In a study enrolling 18 patients with stable angina, 14 patients with unstable angina and non-ST-segment elevation MI, 14 patients with ST-elevation MI, and 16 healthy controls, the progression of CAD was mirrored by increased MMP-9/TIMP-1 ratio in circulating CD14+ monocytes and in serum. Circulating monocytes displayed similar imbalance in the expression of MMP-9 and TIMP-1 in monocyte-derived macrophages within atherosclerotic plaques [Brunner et al.]2010]. Cholesterol lowering 3-HMGcoA reductase inhibitors decrease the tissue expression of various MMPs in atheromatous plaques by attenuating vascular inflammation [Cevik et al., 2008]. For example, rosuvastatin inhibits the expression of MMP-2 and -9 [Guo et al.]2010].
VSMC migration and proliferation is essential for formation of atheromas. MMPs enhance VSMC migration to areas of atherogenesis where they proliferate and enlarge the size of the lesion. Downregulation of both MMP-9 and TNF-α mediate the inhibitory effect of the herb salvia miltorrhia extracts on VSMC migration in RASMCs [Jin et al., 2006a]. An elegant study used mice with genetically modified collagen that resists digestion by MMP collagenases. In an atherogenic background, the lesion size of collagenase-resistant mice was similar in size to controls, but SMC number in the intimal lesions decreased and collagen was more abundant. These findings suggest a role for MMP-mediated collagenolysis in regulating collagen turnover and SMC accumulation in the atheromatous plaque [Fukumoto et al., 2004].
MMP-1 mediates the activation of the PDGFR-β and ERK1/2 atherogenic pathways by ox-LDL [Akiba et al., 2006]. Ox-LDL also activates MMP-2 through upregulation of MT1-MMP and also through oxidative radicals generated by the xanthine/xanthine oxidase complex [Valentin et al., 2005]. AngII plays a role in the pathogenesis of atherosclerosis. AngII increases the expression of MMP-9 in VSMCs via AT1 receptor and NF-κB pathways [Guo et al., 2008]. Thus studies have shown a clear association between MMPs levels, genetic variants of certain MMPs and the atherosclerotic process.
On the basis of the collective ability of MMPs to degrade ECM proteins and the detection of increased MMP protein and activity in vulnerable atherosclerotic plaques, it has been proposed that MMPs reduce the strength of the fibrous cap and contribute to plaque rupture. High-mobility group box 1 is an intracellular gene regulator protein produced by activated VSMCs and causes the progression and vulnerability of atherosclerotic lesions to rupture by stimulating the production of MMP-2, -3 and -9 [Inoue et al., 2007]. Areas of atherosclerotic plaque rupture exhibit a paucity of VSMCs and increased macrophage-derived foam cells. One study compared brachiocephalic artery plaque instability in apoE/MMP-3, apoE/MMP-7, apoE/MMP-9, and apoE/MMP-12 double knockout mice with their age-, strain-, and sex-matched apoE knockout controls. The study concluded that MMP-12 supports lesion expansion and destabilization. MMP-7 had no effect on plaque growth or stability, although it is associated with reduced VSM content in plaques. On the other hand, MMP-3 and -9 appeared to play protective roles, limiting plaque growth and promoting a stable plaque phenotype [Johnson et al., 2005]. MMP-1, -12 and -13 derived from intimal macrophages have been proposed to play a pivotal role in both plaque initiation and progression [Koike et al., 2008]. However, mice with MMP-1-producing macrophages show smaller plaques than control mice and no evidence of plaque rupture [Lemaitre et al., 2001]. These mice have altered MMP-1 from birth, which could reduce collagen accumulation, thus MMPs may be more critical in destabilization of established plaques than in atherogenesis [Newby, 2005]. MMP-3 also appears to have a dual role. While mice lacking both MMP-3 and ApoE show reduced aneurysm formation, they have more extensive atheroma [Silence et al., 2001]. Absence of MMP-3 causes increased collagen and fewer plaque macrophages, a characteristic associated with greater stability in human plaques. Adenoviral gene transfer of TIMP-1 into ApoE−/− mice 6 weeks after commencing a high-fat diet reduced both lesion size and macrophage content, supporting the prevailing concept that MMPs adversely influence established plaques [Rouis et al., 1999]. Estrogen supplementation especially late after menopause may destabilize established plaques, and this could be explained at least in part by estrogen’s ability to upregulate MT1-MMP without a corresponding increase in TIMP-2, thus activating MMP-2. Estrogen also up-regulates MMP-3 in the presence of IL1-β [Grandas et al., 2009]. On the other hand, the ability of MMPs to promote migration and proliferation of VSMCs suggests that MMPs may promote atherosclerotic plaque cap growth and stability. MMPs such as MMP-2, -9, -13 and -14 MMPs release growth factors that are stored in ECM such as TGFh and VEGF. [Mott and Werb, 2004]. MMP-9 releases VEGF bound to proteoglycans in ECM, enhancing its bioavailablity and thereby influencing plaque neovascularization. Collectively, evidence suggests a role for MMPs in regulating plaque stability although the specific roles of individual MMPs are not well established. Further investigation may allow targeting of individual MMPs with specific MMPIs to limit the growth of the atherosclerotic lesions yet promote their stability.
Atherosclerosis in the coronary arteries could lead to acute coronary syndromes [ACS] including unstable anginas and MI. Studies have shown an association between MMPs and the development of ACS [Jones et al., 2003a]. Circulating MMP levels are elevated in patients with ACS. A case-control study on 261 patients who had suffered an MI and 194 healthy controls, all Spanish male smokers, showed that MMP-1 promoter polymorphisms are associated with the risk of early MI [Roman-Garcia et al., 2009]. MMP-2 and -9 were elevated following acute MI in 91 patients compared to 172 control subjects with stable CAD. Higher early levels of MMP-9 were also associated with the extent of left ventricular remodeling and circulating white blood cell levels [Kelly et al., 2007]. Increased MMP expression is also observed after coronary angioplasty, suggesting that MMP expression may be involved in the formation of restenotic lesions [Ikeda and Shimada, 2003]. Whether higher MMP levels induce ACSs or are merely an association is not yet established.
TIMPs also seem to have an association with atherosclerosis. TIMP4 is visible in cardiovascular tissue areas populated by inflammatory cells, mainly macrophages and CD3+ T cells. Human lymphocytes, monocytes, macrophages and mast cells produce TIMP-4. In advanced atherosclerotic lesions, TIMP-4 is detected around necrotic lipid cores, whereas TIMP-3 is detected within and around the core regions indicating different roles in inflammation-induced apoptosis and ECM turnover [Koskivirta et al., 2006]. In a study on 238 men, TIMP-1 was positively associated with carotid intima-media thickness and carotid-femoral pulse-wave velocity using univariate analysis [Zureik et al., 2005]. The mean fibrous cap thickness is greater in individuals with elevated TIMP-1 levels. Also, TIMP-1 is positively associated with measures of lipid core [Gaubatz et al.]2010]. Experimental studies have shown that TIMP-1 deficiency produces macrophage-rich lesions with active proteinases and medial destruction in ApoE−/− mice [Lemaitre et al., 2003]. In TIMP-1-deficient mice atherosclerotic lesions are 30% smaller than in control, but there is an enhanced aneurysm formation [Silence et al., 2002]. However, studies using pharmacological MMPIs did not show any effect on lesion size in atheroma-prone mice [Prescott et al., 1999; Manning et al., 2003].
MMPs and TIMPs levels in early post-MI period may serve as estimates of post-MI cardiac damage and remodeling. MMP-9 and TIMP-1 correlate with echocardiographic parameters of left ventricular [LV] dysfunction after acute MI and may identify patients at risk of subsequent LV remodeling and adverse prognosis [Kelly et al., 2008]. MMPIs have not been used extensively in cardiovascular clinical trials partly because cancer trials showed side effects such as tendonitis [possibly due to inhibition of ADAMs], lack of efficacy, and possible harmful effects [Coussens et al., 2002]. In one clinical trial, 100 patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. Carotid plaques were retrieved by endarterectomy and showed that doxycycline penetrated atherosclerotic plaques with acceptable tissue levels resulting in reduction in MMP-1, but had no effect on atheroma progression [Axisa et al., 2002]. However, most animal studies of post-angioplasty or in-stent stenosis have shown no effect of MMPIs or a catch-up phenomenon after short-term promise.
MMPs may play a role in the pathophysiology of thoracic aortic aneurysm [TAA] and abdominal aortic aneurysm [AAA]. Perhaps the most clinically-relevant association of MMPs has been with aneurysm growth and rupture. Also, there is an association between certain haplotypes of MMP-1, -3, -7, -12 and -13 and the risk of coronary artery aneurysms in patients with Kawazaki disease [Shimizu et al.]2010].
An imbalance between MMPs and TIMPs may represent a major mechanism of TAA formation [Barbour et al., 2007]. High levels of MMP-2 and -9 have been demonstrated in patients with TAA, with MMP-9 predominantly expressed in the faster-growing anterior wall of the aneurysm while MMP-2 is higher in the slower-growing posterior wall [Sinha et al., 2006]. Also, a study of 28 patients with degenerative TAA, 60 patients with thoracic aortic dissection, and 111 control subjects showed an association between a genetic variant of MMP-9 [8202A/G], TAA and dissection [Chen et al., 2006]. Interestingly, different sets of MMPs/TIMPs imbalances were detected in bicuspid and triscuspid aorta patients with TAA [Ikonomidis et al., 2007]. Experimental studies also suggested a role for MMPs in the pathophysiology of TAA. The expression of MT1-MMP, which is important for macrophage-mediated elastolysis, increases progressively after induction of TAA in mice [Jones et al.; Xiong et al., 2008]. Elevated levels of MMP-2, -8, -9 and -12 are detected at various stages of TAA development in mice [Barbour et al., 2006]. Also, induction of TAA formation in rats is associated with increased levels of MMP-2 and -9, and ADAM-10 and -17 [Geng et al.]. In the mouse model of Marfan syndrome, TAA was prevented in mice treated with the MMPI doxycycline, while mild aneurysm was evident in mice treated with the β-blocker atenolol. Doxycycline improved elastic fiber integrity, normalized aortic stiffness, and prevented vessel weakening. Also, the impaired vascular contraction and endothelium-dependent relaxation observed in the nontreated and atenolol mice was improved with doxycycline [Chung et al., 2008].
MMPs could also play a role in the pathophysiology of AAA. The histopathological changes of aneurysmatic aorta are mostly seen in tunica media and intima and include accumulation of lipids in foam cells, extracellular free cholesterol crystals, calcifications, thrombosis, ulcerations and rupture of the vascular layers. There is also an adventitial inflammatory infiltrate. Degradation of tunica media is a major pathophysiologic mechanism in AAA. Loss of elastin could be an initiating event in AAA formation, while loss of collagen is required for continued expansion. Medial neovascularization is characteristic of established AAA and involves proteolytic degradation of ECM by MMPs to facilitate EC proliferation and migration. Studies demonstrated upregulation of pro-angiogenic cytokines and increased medial neovascularization at the aneurysm rupture edge. Growth and rupture of AAA result from increased collagen turnover [Choke et al., 2006].
MMP-2 and -9 appear to play a role in AAA formation [Petersen et al., 2000; Goodall et al., 2001]. In patients with AAA, plasma levels of MMP-2 and -9 are elevated in the range of 0.06–0.6 μg/ml [Hovsepian et al., 2000; Goodall et al., 2001; Nagashima et al., 2002]. MMP-9 is the most abundantly expressed MMP in AAA and is produced mainly by the aneurysm-infiltrating macrophages [Sakalihasan et al., 1996]. The plasma level and aortic wall expression of MMPs are especially elevated in patients with imminent aneurysm rupture. MMP-1 and -9 levels are elevated in the plasma of patients with ruptured AAA versus non-ruptured AAA. A 4-fold elevation in preoperative plasma MMP-9 were associated with non-survival at 30 days from rupture surgery compared with surviving patients for greater than 30 days [Wilson et al., 2008a]. Elevation of MMP-9 was also associated with ruptured aneurysm related 30-day mortality. Secretion of MMP-2 and -9 by HASMC is enhanced in tissues of AAA in response to hypoxia [Erdozain et al.]2010]. Also, MMP-2 and -9 are necessary to induce experimental AAA formation in mice [Longo et al., 2002], and targeted gene disruption of MMP-9 in mice suppresses the development of AAA [Pyo et al., 2000]. MMP-8 may also have a role in AAA formation. High levels of MMP-8 were found in infrarenal aortic biopsies taken from AAA. Immunohistochemistry studies localized MMP-8 to mesenchymal cells within the adventitia of the aortic wall [Wilson et al., 2005]. A localized increase in MMP-8 and -9, mediated by native mesenchymal cells, was shown in biopsies from aneurysm rupture sites compared with their paired anterior wall biopsies.
The identification of the potential role of MMPs in the pathogenesis of AAA has prompted the measurement of MMPs for estimation of aneurysmal area and matrilytic activity [Razavian et al.]2010]. Plasma MMP-9 levels are associated with aneurysmal size and expansion [Hackmann et al., 2008]. In another study, MMP-9 plasma levels were determined in peripheral venous blood from 25 patients with AAA, 15 patients with atherosclerotic occlusive disease, and 5 control subjects. MMP-9 levels were directly compared with the amount of MMP-9 produced in aortic tissue. Elevated MMP-9 levels were observed in one half of patients with AAA and less than 10% of those with atherosclerotic occlusive disease [positive predictive value, 92.3%]. Plasma MMP-9 levels in AAA patients appear to directly reflect the amount of MMP-9 produced within aneurysm tissue, and MMP-9 levels decrease substantially after aneurysm repair [Hovsepian et al., 2000]. A meta-analysis of data on 580 AAA cases and 258 controls concluded that an elevated MMP-9 has 48% sensitivity and 95% specificity as a diagnostic screening test for the presence of AAA [Sangiorgi et al., 2001]. However, normal MMP-9 levels may not exclude the presence of AAA [negative predictive value, 52%]. Also, some studies demonstrated no significant correlation between MMP-9 serum levels and AAA diameter [Eugster et al., 2005; van Laake et al., 2005; Cui et al., 2006; Wilson et al., 2006] or between the plasma and aneurysm wall concentrations of any MMP or TIMP and AAA diameter [Wilson et al., 2008b]. Further investigation is necessary to explore the validity and accuracy of MMP-9 and other MMPs as investigative tools of AAA.
Studies have investigated whether genetic variants of MMPs are associated with AAA risk. A study in 51 patients with AAA and 48 controls showed that variations in MMP-2 gene do not contribute to the development of AAA [Hinterseher et al., 2006]. In contrast, a study enrolling 414 AAA patients and 203 control subjects showed an association between the T allele of the C-1562T functional promoter polymorphism of the MMP-9 gene and AAA formation [Jones et al., 2003b]. Another study enrolling 146 AAA patients and 156 healthy individuals showed no association between MMP-9 and AAA [Armani et al., 2007]. A meta-analysis of 6 gene polymorphisms [ACE I/D, MTHFR+677C>T, MMP9-1562C>T, IL-1β/3953C>T, eNOS 4a/4b and TIMP-1/+434C>T] reported in multiple case control studies, showed that 3 of these polymorphisms, ACE RR 1.33 [95% CI 1.20–1.48], MTHFR RR 1.14 [1.08–1.21] and MMP-9 RR 1.09 [1.01–1.18], were associated with a significant risk of AAA [Thompson et al., 2008]. Further investigation of the MMP polymorphisms may offer prophylactic measures to individuals genetically prone to the development of AAA.
The mechanism of action of MMPs in aneurysm formation has largely been attributed to their proteolytic effects on ECM proteins and subsequent weakening of the aortic wall. MMP-2 has the greatest elastolytic activity and is produced mainly by VSMCs and fibroblasts [Wall et al., 2003]. Additional inhibitory effects of MMP-2 and -9 on Ca2+-dependent mechanism of aortic VSM contraction may play a role in the early development of aneurysm [Chew et al., 2004]. MMP-9 is a more potent inhibitor of aortic contraction than MMP-2, consistent with the dominant MMP-9 expression in AAA wall [Sakalihasan et al., 1996]. Aortic VSM contractile function may contribute to the structural integrity of the aortic wall and limit its tendency to dilate in response to pulsatile forces generated with each cardiac cycle. Atrophy of the tunica media and depletion of VSMCs are consistent histological findings in AAA [Lopez-Candales et al., 1997]. Also, disruption of structural integrity of the tunica media e.g. in chronic aortic dissection, often leads to late aneurysm formation. MMP-induced inhibition of VSM contraction may function synergistically with their degradation of ECM, causing further weakening of the aortic wall and aneurysm formation.
Studies have investigated the effect of MMPIs on AAA growth and rupture. Small RCTs suggested favorable effects of doxycycline on retarding AAA expansion [Mosorin et al., 2001]. One study demonstrated that two weeks doxycycline treatment in patients with advanced AAA resulted in selective reduction of aortic wall neutrophil and cytotoxic T-cell content, and suppression of inflammatory markers including cytokines IL-6 and IL-8 and transcription factors AP-1, C/EBP and STAT3 [Lindeman et al., 2009]. In another study, patients undergoing endovascular AAA repair were randomized to doxycycline or placebo for 6 months following the procedure. Plasma MMP-9 decreased below baseline in doxycycline treated patients while there was a nonsignificant increase in the placebo group. In patients with endoleaks at 6 months, plasma MMP-9 increased in 83% of the placebo group, but in only 14% of doxycycline-treated group. Among endoleak-free patients with AneuRx or Excluder endografts, doxycycline caused greater decreases in maximum aortic diameter and the aortic neck dilatation than placebo [Hackmann et al., 2008]. The use of MMPIs as therapeutic tools in AAA is perhaps the most promising clinical application of MMPIs in vascular medicine.
Embryo implantation and trophoblast invasion are tightly regulated processes involving interaction between maternal decidual cells and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by many factors including MMPs. Decidual cells secrete the highest levels of MMPs and their invasive potential increases in the presence of cytotrophoblast [Cohen et al.]2010]. Studies have shown that the endometrium produces proMMP-2, -3, -7, -9, and active MMP-2 [Jones et al., 2006]. MMPs may also be involved in placental remodeling throughout pregnancy. MMP-9 levels are higher in normal pregnant than non-pregnant women, with positive correlation with the gestational period [Montagnana et al., 2009]. In first trimester human placenta, MMP-2 expression/activity is observed in extravillous trophoblasts and MMP-9 mainly in villous cytotrophoblasts. The invasive ability of early cytotrophoblasts is inhibited by TIMP-2 and anti-MMP-2 antibody, suggesting a role of gelatinases, especially MMP-2. This is supported by reports of polarized release of MMP-2 and -9 from cultured human placental syncytiotrophoblasts. In full-term placental tissue, MMP-2 expression in the extravillous trophoblasts is similar to that in first trimester, but the gelatinase activity is decreased or completely lost [Sawicki et al., 2000]. MMP-2 also seems to mediate the protease activity of uterine natural killer cells which regulate trophoblast invasion and spiral artery remodeling in early placentation [Naruse et al., 2009]. PKC-α may be responsible for the regulation of MMP-2 expression during decidualization [Tsai et al., 2009]. EMMPRIN relase from the luminal epithelium may regulate the expression of stromal MMP-2 and -14, and thereby affect the adhesion and fusion of embryo to luminal epithelium [Mishra et al.]2010]. Increased plasma levels of MMPs are also detected during normal pregnancy, suggesting a role for MMPs in the pregnancy-associated changes in vascular function [Merchant and Davidge, 2004].
Experimental studies supported a role of MMPs during pregnancy. The serum activity of MMP-2 and -9 is higher in pregnant than non-pregnant bitches, and is correlated with the serum levels of estrogen [Schafer-Somi et al., 2005]. Furin is highly expressed in placental villi of rhesus monkeys and humans during early pregnancy. In HTR8/SVneo cells, knocking-down furin expression inhibits cell invasion and migration, and decreases MMP-9 activity. In contrast, overexpression of furin is associated with increased cell invasion and migration, and MMP-9 activity [Zhou et al., 2009]. MMP-26 mRNA is expressed in the mouse uterus during the estrous cycle and early pregnancy [Liu et al., 2005], while TIMP-2 mRNA is upregulated in the endometrium during the luteal phase of the estrous cycle and during early pregnancy in cows [Ledgard et al., 2009].
MMPs could also play a role in the uterine artery remodeling during pregnancy. MMP-2, MT1-MMP, MMP-3 and TIMP-1 transcripts are elevated in the uterine artery of early pregnant rats [day 7]. In late pregnant rats [day 21], the mRNA expression of MMP-2, -3, -7, -9, -12, -13, MT1-MMP, and TIMP-1 and -2 are increased. TIMP-1 and MMP-3 mRNA expression return to virgin control levels in the post-partum period, whereas MMP-9 and -13 remain elevated or increase further. Maximum elevation of MMP-2 is observed at day 21 of gestation, suggesting a role in maintaining uterine blood flow in late pregnancy. Continued elevatation of the levels of some MMPs post-partum may contribute to vessel regression and return to a non-pregnant state [Kelly et al., 2003]. Increased mRNA and protein expression of pro- and active MMP-2 was also observed in renal and mesenteric arteries from pregnant compared with virgin rats [Jeyabalan et al., 2006]. It has also been suggested that vascular gelatinase activity may function upstream of the endothelial endothelin B [ETB] receptor and the NO pathway in the renal vasodilatory response during pregnancy [Jeyabalan et al., 2007].
Modification of the fine balance between MMPs and MMPIs may play a role in the vascular changes associated with complications of pregnancy such as preeclampsia [PE]. PE is characterized by HTN and proteinuria and may lead to eclampsia, convulsions, cerebral hemorrhage, HELLP syndrome, and placental abruption. The pathogenesis of PE is unclear, but inadequate blood supply to the placenta may stimulate the release of mediators such as cytokines and growth factor inhibitors leading to endothelial cell damage and vascular inflammation. Abnormalities in the maternal immune system and inadequate gestational immune tolerance may also contribute to the development of PE. Placental hypoxia may increase the release of fetal mediators into the maternal circulation leading to an immune response, endothelial damage and ultimately PE [Maynard et al., 2003].
MMP-mediated vascular remodeling may play a role in the pathogenesis of PE [Merchant and Davidge, 2004]. Higher levels of MMPs such as MMP-2 and lower levels of TIMPs have been shown in women with PE [Narumiya et al., 2001; Montagnana et al., 2009; Shokry et al., 2009] or who subsequently develop PE [Myers et al., 2005; Lavee et al., 2009]. Increased MMP-2 activity may contribute to the endothelial dysfunction in PE [Myers et al., 2005]. However, the proteases intrinsic to syncytiotrophoblast microvillous membranes [STBM] are unlikely to be the cause of the endothelial changes [de Jager et al., 2003]. A recent study investigating 128 cases of PE and 569 control pregnancies showed higher serum levels of MMP-9 in PE than controls, and an association between serum MMP-9 and TNF-receptor levels, suggesting an underlying inflammatory process [Poon et al., 2009]. MMP-7 and -26 may contribute to ECM remodeling in the umbilical cord of PE pregnancies by activating MMP-9. The high MMP-9 activity may enhance the proteolytic release of growth factors from their complexes with ECM components, thus facilitating their interaction with membrane receptors, and stimulation of cell division and ECM synthesis [Galewska et al.; Galewska et al., 2008]. These findings have suggested MMP-9 as one of the biomarkers of PE [Poon et al.] 2010].
MMPIs have been used to study the role of MMPs in PE. In a study on hypertensive and control pregnant rats, doxycycline treatment from gestational day 12 to day 18 resulted in intrauterine growth retardation and lighter placentas in both groups. Hypertensive pregnant rats exhibited a deeper endovascular trophoblast invasion. Doxycycline treatment in PE rats was associated with reduction in trophoblast invasion, spiral artery remodeling as assessed by the deposition of fibrinoid and α-actin in the spiral artery contour, and the vascularity index as assessed by measurement of placental perfusion [Geusens et al.]2010].
Some studies suggest different role of MMPs in gestational HTN as compared to PE. Higher plasma pro-MMP-9 levels and pro-MMP-9/TIMP-1 ratios were demonstrated in women with gestational HTN, but not in PE [Palei et al.]2010]. Also, the C[-1562]T polymorphism in MMP-9 gene showed an association with gestational HTN, but not PE [Palei et al.]2010]. Other studies demonstrated reduced levels of MMPs and elevated TIMPs in PE and suggested that reduced degradation of ECM components results in intimal thickening, tissue hypoxia and eventual PE cascade. Decreased amount and activity of MMP-1 and elevated amounts of TIMP-1 were detected in PE umbilical cord arteries [Galewska et al., 2006]. Also, in cultured human decidual ECs, basal and stimulated secretion of MMP-1 was higher in normal compared with PE ECs. The lower MMP-1 expression of decidual ECs from PE women may inhibit endovascular invasion by cytotrophoblasts. These findings may partly explain the relative failure of trophoblasts to invade maternal decidual blood vessels in PE pregnancy [Gallery et al., 1999]. Lower levels of MMP-1, -9 and -3 were also detected in extracts of human umbilical cord artery. MMP-2 is the main collagenolytic enzyme in umbilical cord artery [UCA] wall. PE was associated with a distinct reduction in those MMPs content and activity, which may reduce the breakdown of collagen in the arterial wall. The accumulation of collagen with simultaneous reduction in elastin content of UCA may reduce the elasticity of arterial wall and decreases the blood flow to the fetus [Galewska et al., 2003]. MMP-3 expression levels are also reduced in the placental invasive trophoblasts of patients with severe PE [Husslein et al., 2009].
A maternal immune cell network accumulating in the placental bed may alter the cytokine environment, resulting in disturbed trophoblast cell function, impaired MMP expression and reduced invasiveness. Expression of MMP-3 and -7 by extravillous trophoblasts is reduced in PE patients, especially close to spiral arteries. In contrast to healthy pregnancies, in PE extravillous trophoblasts strongly express the receptor for leukemia inhibitory factor [LIF]. LIF suppresses MMP-expression and is produced by uterine natural killer cells which accumulate alongside the spiral arteries in the placental bed of PE patients [Reister et al., 2006]. MMP-9 expression is also low in PE pregnancies [Shokry et al., 2009].
TIMP-1 is elevated in PE [Tayebjee et al., 2005; Montagnana et al., 2009]. Also, mean amniotic TIMP-2 levels are higher in women who developed a hypertensive disorder compared to normotensive women [Lavee et al., 2009; Montagnana et al., 2009]. A decrease in ECM remodeling could play a role in HELLP syndrome. The mRNA expression of MMP-2 and TIMP-2 are decreased, whereas TIMP-1 and -3 levels are unchanged in 11 females with HELLP syndrome and 8 controls matched for gestational age [von Steinburg et al., 2009].
Some studies showed no association between MMP levels and HTN in pregnancy. A study enrolling 133 women showed no statistical difference in MMP-2 levels between patients with gestational HTN and normotensive controls [Lavee et al., 2009] or between PE and normotensive women [Galewska et al., 2008]. Another study enrolling 83 pregnant women showed no difference in pro-MMP-2 levels [Palei et al., 2008]. Also, some studies showed no statistical difference in TIMP-1 and -2 between PE and control samples [Galewska et al., 2008]. Collectively, studies showed an imbalance between MMPs and TIMPs in HTN in pregnancy, but the mechanisms via which these imbalances contribute to the pathogenesis of the disease need to be further examined.
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Members of the MMP Family and their Substrates
| Collagenases | ||||
| MMP-1 [Collagenase-1] | Fibroblast, Interstitial, Tissue Collagenase | I, II, III, VII, VIII, X, and gelatin | Aggrecan, casein, nidogen, serpins, versican, perlecan, proteoglycan link protein, tenascin-C | α1-antichymotrypsin, α1-antitrypsin, α1-proteinase inhibitor, IGFBP-3, IGFBP-5, IL-1β, L-selectin, ovostatin, recombinant TNF-α peptide, SDF-1 |
| MMP-8 [Collagenase-2] | Neutrophil, or PMNL Collagenase | I, II, III, V, VII, VIII, X | Aggrecan, laminin, nidogen | α2-antiplasmin, pro-MMP-8 |
| MMP-13 [Collagenase-3] | VV, SMC, preeclampsia | I, II, III, IV | Aggrecan, fibronectin, laminin, perlecan, tenascin | Plasminogen activator 2, pro-MMP-9, pro-MMP-13, SDF-1 |
| Gelatinases | ||||
| MMP-2 [Gelatinase-A] | Aortic aneurysm, VV | I, II, III, IV, V, VII, X, XI | Aggrecan, elastin, fibronectin, laminin, nidogen, proteoglycan link protein, versican | Active MMP-9, active MMP-13, FGF R1, IGF-BP3, IGF-BP5, IL-1β, recombinant TNF-α peptide, TGF-β |
| MMP-9 [Gelatinase-B] | Aortic aneurysm, VV | IV, V, VII, X, XIV | Fibronectin, laminin, nidogen, proteoglycan link protein, versican | CXCL5, IL-1β, IL2-R, plasminogen, pro-TNFα, SDF-1, TGF-β |
| Stromelysins | ||||
| MMP-3 [Stromelysin-1] | VSMC, coronary artery disease, hypertension, tumor invasion | II, III, IV, IX, X, XI | Aggrecan, casein, decorin, elastin, fibronectin, laminin, nidogen, perlecan, proteoglycan, proteoglycan link protein, versican | α1-antichymotrypsin, α1-proteinase inhibitor, antithrombin III, E-cadherin, fibrinogen, IGF-BP3, L-selectin, ovostatin, pro-HB-EGF, pro-IL-1β, pro-MMP-1, pro-MMP-8, pro-MMP-9, pro-TNFα, SDF-1 |
| MMP-10 [Stromelysin-2] | Atherosclerosis, uterine, preeclampsia | III, IV, V | Fibronectin, laminin, nidogen | Pro-MMP-1, pro-MMP-8, pro-MMP-10 |
| Matrilysins | ||||
| MMP-7 [Matrilysin-1] | Uterine MMP | IV, X | Aggrecan, casein, elastin, enactin, laminin, proteoglycan link protein | β4 integrin, decorin, defensin, E-cadherin, Fas-L, plasminogen, pro-MMP-2, pro-MMP-7, pro-MMP-8, pro-TNFα, transferrin, and syndecan α2-antiplasmin |
| MMP-26 [Matrilysin-2, endometase] | Breast cancer cells | IV, gelatin | Casein, fibrinogen, fibronectin | Fibrin, fibronectin Pro-MMP-2 β 1-proteinase inhibitor |
| Membrane-Type MMPs | ||||
| MMP-14 [MT1-MMP] | Human fibroblasts, SMC, VSMC, uterine, angiogenesis | I, II, III | Aggrecan, dermatan proteoglycan, fibrin, fibronectin, laminin, nidogen, perlecan, tenascin, vitronectin | αvβ3 integrin, CD44, gC1qR, pro-MMP-2, pro-MMP-13, pro-TNFα, SDF-1, tissue transglutaminase |
| MMP-15 [MT2-MMP] | Human fibroblasts, leukocytes, preeclampsia | I | Aggrecan, fibronectin, laminin, nidogen, perlecan, tenascin, vitronectin | Pro-MMP-2, pro-MMP-13, tissue transglutaminase |
| MMP-16 [MT3-MMP] | Human leukocytes, angiogenesis | I | Aggrecan, casein, fibronectin, laminin, perlecan, vitronectin | Pro-MMP-2, pro-MMP-13 |
| MMP-24 [MT5-MMP] | Leukocytes | Chondroitin sulfate, dermatin sulfate, fibronectin | Pro-MMP2, pro-MMP-13 | |
| Other MMPs | ||||
| MMP-11 [Stromelysin-3] | Angiogenesis, uterine | Does not cleave | Laminin | α1-antitrypsin, α1-proteinase inhibitor, IGFBP-1 |
| MMP-12 [metalloelastase] | Macrophages | IV | Elastin | Plasminogen |
| MMP-19 [RASI-1] | I, IV, gelatin | Aggrecan, casein, fibronectin, laminin, nidogen, tenascin | ||
| MMP-20 [Enamelysin] | Tooth enamel | Aggrecan, amelogenin, cartilage oligomeric protein | ||
| MMP-21 | Macrophages, Fibroblasts, human placenta | α1-antitrypsin | ||
| MMP-23 [CA-MMP] | Ovary, testis, prostate | Gelatin | ||
| MMP-25 [Leukolysin, MT6-MMP] | IV, gelatin | Fibrin, fibronectin, pro-MMP-2 | ||
| MMP-28 [Epilysin] | Casein |