doi: 10.1161/01.RES.0000070112.80711.3D
© 2003 American Heart Association, Inc.
Review |
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Structure, Function, and Biochemistry
From the Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, UK.
Correspondence to Dr Hideaki Nagase, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Rd, London W6 8LH, UK. E-mail h.nagase{at}imperial.ac.uk
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Abstract |
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 Top Abstract IntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.
Key Words: extracellular matrix • protease • protease inhibitors
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Introduction |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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Extracellular matrix (ECM) macromolecules are important for creating the cellular environments required during development and morphogenesis. Matrix metalloproteinases (MMPs), collectively called matrixins, are proteinases that participate in ECM degradation.1,2 Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, activation of the precursor zymogens, interaction with specific ECM components, and inhibition by endogenous inhibitors.1,2 A loss of activity control may result in diseases such as arthritis, cancer, atherosclerosis, aneurysms, nephritis, tissue ulcers, and fibrosis.3 Tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of matrixins that participate in controlling the local activities of MMPs in tissues.4,5 The pathological effects of MMPs and TIMPs in cardiovascular disease processes that involve vascular remodeling, atherosclerotic plaque instability, and left ventricular remodeling after myocardial infarction are of considerable interest and are covered by other reviews in this series.6–8 In the present review, we give an overview of structure, function, and biochemistry of MMPs and TIMPs.
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Members of the Matrixin Family |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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The first MMP activity discovered was a collagenase in the tail of a tadpole undergoing metamorphosis. To date, 24 different vertebrate MMPs have been identified, of which 23 are found in humans. Matrixins are also found in Hydra,9 sea urchin,10 and Arabidopsis.11 The sequence homology with collagenase 1 (MMP-1), the cysteine switch motif PRCGXPD in the propeptide that maintains MMPs in their zymogen form (proMMP), and the zinc-binding motif HEXGHXXGXXH in the catalytic domain are the signatures used to assign proteinases to this family. The exception is MMP-23, which lacks the cysteine switch motif, but its amino acid sequence of the catalytic domain is related to MMP-1. MMPs generally consist of a prodomain, a catalytic domain, a hinge region, and a hemopexin domain (see Figure 1). They are either secreted from the cell or anchored to the plasma membrane. On the basis of substrate specificity, sequence similarity, and domain organization, vertebrate MMPs can be divided into six groups (see Figure 1 and Table 1), as described below. An extended version of Table 1, including MMP substrates, is available in the online data supplement (available at http://www.circresaha.org).
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Collagenases
MMP-1, MMP-8, MMP-13, and MMP-18 (Xenopus) are in this group. The key feature of these enzymes is their ability to cleave interstitial collagens I, II, and III at a specific site three-fourths from the N-terminus. Collagenases can also digest a number of other ECM and non-ECM molecules.
Gelatinases
Gelatinase A (MMP-2) and gelatinase B (MMP-9) belong to this group. They readily digest the denatured collagens, gelatins. These enzymes have three repeats of a type II fibronectin domain inserted in the catalytic domain, which bind to gelatin, collagens, and laminin.12 MMP-2, but not MMP-9, digests type I, II, and III collagens.13,14 Although MMP-2 null mice develop without any apparent abnormality,15 mutations in human MMP-2 resulting in the absence of active enzyme are linked with an autosomal recessive form of multicentric osteolysis, a rare genetic disorder that causes destruction and resorption of the affected bones.16 This suggests that MMP-2 in humans is important for osteogenesis.16
Stromelysins
Stromelysin 1 (MMP-3) and stromelysin 2 (MMP-10) both have similar substrate specificities, but MMP-3 has a proteolytic efficiency higher than that of MMP-10 in general. Besides digesting ECM components, MMP-3 activates a number of proMMPs, and its action on a partially processed proMMP-1 is critical for the generation of fully active MMP-1.17 MMP-11 is called stromelysin 3, but it is usually grouped with "other MMPs" because the sequence and substrate specificity diverge from those of MMP-3.
Matrilysins
The matrilysins are characterized by the lack of a hemopexin domain. Matrilysin 1 (MMP-7) and matrilysin 2 (MMP-26),18 also called endometase,19 are in this group. Besides ECM components, MMP-7 processes cell surface molecules such as pro–
-defensin, Fas-ligand, pro–tumor necrosis factor (TNF)-, and E-cadherin. Matrilysin 2 (MMP-26) also digests a number of ECM components.
Membrane-Type MMPs
There are six membrane-type MMPs (MT-MMPs): four are type I transmembrane proteins (MMP-14, MMP-15, MMP-16, and MMP-24), and two are glycosylphosphatidylinositol (GPI) anchored proteins (MMP-17 and MMP-25). With the exception of MT4-MMP, they are all capable of activating proMMP-2. These enzymes can also digest a number of ECM molecules, and MT1-MMP has collagenolytic activity on type I, II, and III collagens.20 MT1-MMP null mice exhibit skeletal abnormalities during postnatal development that are most likely due to lack of collagenolytic activity.21 MT1-MMP also plays an important role in angiogenesis.22 MT5-MMP is brain specific and is mainly expressed in the cerebellum.23 MT6-MMP (MMP-25) is expressed almost exclusively in peripheral blood leukocytes and in anaplastic astrocytomas and glioblastomas but not in meningiomas.24,25
Other MMPs
Seven MMPs are not classified in the above categories. Metalloelastase (MMP-12) is mainly expressed in macrophages26 and is essential for macrophage migration.27 Besides elastin, it digests a number of other proteins.
MMP-19 was identified by cDNA cloning from liver28 and as a T-cell–derived autoantigen from patients with rheumatoid arthritis (RASI).29
Enamelysin (MMP-20), which digests amelogenin, is primarily located within newly formed tooth enamel. Amelogenin imperfecta, a genetic disorder caused by defective enamel formation, is due to mutations at MMP-20 cleavage sites.30
MMP-22 was first cloned from chicken fibroblasts,31 and a human homologue has been identified on the basis of EST sequences. The function of this enzyme is not known.
MMP-23, also called cysteine array MMP, is mainly expressed in reproductive tissues.32 The enzyme lacks the cysteine switch motif in the prodomain. It also lacks the hemopexin domain; instead, it has a cysteine-rich domain followed by an immunoglobulin-like domain. It is proposed to be a type II membrane protein harboring the transmembrane domain in the N-terminal part of the propeptide. Because it has a furin recognition motif in the propeptide, it is cleaved in the Golgi and released as an active enzyme into the extracellular space.33
The latest addition to the MMP family is epilysin, or MMP-28, mainly expressed in keratinocytes.34,35 Expression patterns in intact and damaged skin suggest that MMP-28 might function in tissue hemostasis and wound repair.34–36
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Three-Dimensional (3D) Structures of MMPs |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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X-ray crystallography and nuclear magnetic resonance (NMR) have determined the 3D structures of a number of MMPs (Table 1). The structure of the prodomain is known for MMP-2, MMP-3, and MMP-9. It consists of three
-helices and connecting loops (see Figure 2B). The first loop between helix 1 and 2 is a protease-sensitive "bait region." An extended peptide region after helix 3 lies in the substrate-binding cleft of the catalytic domain. This region contains the conserved cysteine switch, which forms a fourth ligand of the active-site zinc, keeping the zymogen inactive. It is notable that the orientation of the propeptide backbone as it interacts with the active-site cleft is opposite that of a peptide substrate. However, the hydrogen bonds that it makes with the active site are identical to those of a substrate backbone.37
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The polypeptide chain folds of the catalytic domains are essentially superimposable. The chain consists of a 5-stranded ß-pleated sheet, three -helices, and connective loops (see Figure 2C). This proteinase domain contains one catalytic zinc, one structural zinc, and, generally, three calcium ions. The substrate-binding cleft is formed by strand IV, helix B, and the extended loop region after helix B. Three histidines coordinate the active-site zinc. The loop region contains the conserved "Met-turn," a base to support the structure around the catalytic zinc.38 The fourth ligand of the catalytic zinc is a water molecule. The glutamic acid adjacent to the first histidine is essential for catalysis.
In the orientation shown in Figure 2C, a substrate binds into the catalytic site cleft from left to right with respect to its N- and C-termini, and the carbonyl group of the peptide bond coordinates with the active-site zinc. This displaces the water molecule from the zinc atom. The peptide hydrolysis is assisted by the carboxyl group of the glutamate, which serves as a general base to draw a proton from the displaced water molecule, thereby facilitating the nucleophilic attack of the water molecule on the carbonyl carbon of the peptide scissile bond. A pocket to the right of the active-site zinc, called the specificity pocket or S1' pocket, accommodates the side chain of the substrate residue, which becomes the new N-terminus after cleavage. The sizes of the S1' pocket vary among the MMPs, and this is one of the major determining factors of substrate specificity.39
Three repeats of fibronectin type II domains found in MMP-2 and MMP-9 are inserted between the fifth ß-strand and the catalytic site helix40 (Figures 2A and 2D). The structure of each fibronectin domain consists of two antiparallel ß-sheets, connected with a short -helix and stabilized by two disulfide bonds. NMR studies have indicated that domains 2 and 3 are quite flexible, possibly interacting simultaneously with multiple sites in the ECM.41
The hemopexin domains have a 4-bladed ß-propeller fold, with a single stabilizing disulfide bond between blades I and IV (Figure 2E). The hemopexin domains of MMP-9 form an asymmetric homodimer through blade IV.42 The asymmetry is the result of shifts in blade III and IV structure on dimerization, which alters its physicochemical properties.42 The hemopexin domain of MMP-9 binds the C-terminal domain of TIMP-1.43 However, the formations of this complex and the MMP-9 dimer are mutually exclusive, probably because of an overlap in the TIMP-1–binding site and the dimer interface.42 The recombinant MMP-9 hemopexin domain binds to gelatin and is able to inhibit the invasion of melanoma cells.44 TIMP-2 binds to the hemopexin domain of proMMP-2. The crystal structure of this complex45 (Figure 2A) shows that this interaction is through the C-terminal domain of TIMP-2 and blades III and IV of the hemopexin domain; the N-terminal inhibitory domain of TIMP-2 is free to interact with other MMPs.
ß-Propeller domains with a larger number of blades are found in other proteins, such as heterotrimeric G proteins, clathrin, and the -subunit of integrins. These domains often mediate protein-protein interactions.46 Depending on the specific MMP, the hemopexin-like domain is important for substrate specificity and is required for proMMP-2 activation and the dimerization of MT1-MMP and MMP-9.
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Activation of ProMMPs |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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Stepwise Activation Mechanism
MMPs can be activated by proteinases or in vitro by chemical agents,47 such as thiol-modifying agents (4-aminophenylmercuric acetate, HgCl2, and N-ethylmaleimide), oxidized glutathione, SDS, chaotropic agents, and reactive oxygens (see Figure 3). Low pH and heat treatment can also lead to activation. These agents most likely work through the disturbance of the cysteine-zinc interaction of the cysteine switch.48,49 Studies of proMMP-3 activation with a mercurial compound have indicated that the initial cleavage occurs within the propeptide and that this reaction is intramolecular rather than intermolecular.50 The subsequent removal of the rest of the propeptide is due to intermolecular reaction of the generated intermediates.50,51 Recently, studies by Gu et al52 have shown that NO activates proMMP-9 during cerebral ischemia by reacting with the thiol group of the cysteine switch and forming an S-nitrosylated derivative,52 a demonstration of the chemical activation of a proMMP in vivo.
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Proteolytic activation of MMPs is stepwise in many cases47 (see Figure 3). The initial proteolytic attack occurs at an exposed loop region between the first and the second helices of the propeptide. The cleavage specificity of the bait region is dictated by the sequence found in each MMP. Once a part of the propeptide is removed, this probably destabilizes the rest of the propeptide, including the cysteine switch–zinc interaction, which allows the intermolecular processing by partially activated MMP intermediates or other active MMPs.17,51 Thus, the final step in the activation is conducted by an MMP.
Activation of proMMPs by plasmin is a relevant pathway in vivo. Plasmin is generated from plasminogen by tissue plasminogen activator bound to fibrin and urokinase plasminogen activator bound to a specific cell surface receptor. Both plasminogen and urokinase plasminogen activator are membrane-associated, thereby creating localized proMMP activation and subsequent ECM turnover. Plasmin has been reported to activate proMMP-1, proMMP-3, proMMP-7, proMMP-9, proMMP-10, and proMMP-13.53 Activated MMPs can participate in processing other MMPs. The stepwise activation system may have evolved to accommodate finer regulatory mechanisms to control destructive enzymes, inasmuch as TIMPs may interfere with activation by interacting with the intermediate MMP before it is fully activated.54
Intracellular Activation
Most proMMPs are secreted from cells and activated extracellularly. Pei and Weiss55 first demonstrated that proMMP-11 (stromelysin 3) is activated intracellularly by furin. ProMMP-11 possesses a furin recognition sequence, KX(R/K)R, at the C-terminal end of the propeptide. Several other MMPs, including the six MT-MMPs,2,56 MMP-23, and epilysin (MMP-28),34,35 have a similar basic motif in the propeptide. Because these proteins are most likely secreted as active enzymes, their gene expression and inhibition by endogenous inhibitors would be critical for the regulation of activity.
Cell Surface Activation of ProMMP-2
ProMMP-2 is not readily activated by general proteinases. The main activation of proMMP-2 takes place on the cell surface and is mediated by MT-MMPs. This includes MT1-MMP, MT2-MMP,57 MT3-MMP,58 MT5-MMP,59,60 and MT6-MMP.24 MT4-MMP does not activate proMMP-2.61
MT1-MMP–mediated activation of proMMP-2 has been studied extensively. The unique aspect is that it requires the assistance of TIMP-2.62–64 ProMMP-2 forms a tight complex with TIMP-2 through their C-terminal domains, therefore permitting the N-terminal inhibitory domain of TIMP-2 in the complex 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. This MT1-MMP–TIMP-2–proMMP-2 complex is then presented to an adjacent free MT1-MMP for activation. Clustering of MT1-MMP on the cell surface through interactions of the hemopexin domain facilitates the activation process65 (see Figure 4). Jo et al66 reported that the maximum enhancement of proMMP-2 activation is observed at a TIMP-2/MT1-MMP ratio of 0.05, suggesting that a large number of free MT1-MMP may surround the ternary complex of proMMP-2–TIMP-2–MT1-MMP for effective proMMP-2 activation.
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ProMMP-2 activation by MT2-MMP is direct and independent of TIMP-2.67 Interestingly, TIMP-4 binds to the proMMP-2 hemopexin domain, and it inhibits MT1-MMP, but it does not result in proMMP-2 activation by MT1-MMP.68 The reason for this is not clear, but it may be due to an incorrect molecular assembly with TIMP-4.
MT1-MMP also activates proMMP-13 on the cell surface; this activation is more efficient in the presence of active MMP-2.69 The activation of proMMP-13 by MT1-MMP is independent of TIMP-2 but requires the C-terminal hemopexin domain of proMMP-13.70
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Substrate Specificity of MMPs |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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Substrate specificities of MMPs have been studied either by identifying the cleavage sites of protein substrates or by a series of synthetic peptide substrates.71 In general, MMPs cleave a peptide bond before a residue with a hydrophobic side chain, such as Leu, Ile, Met, Phe, or Tyr. A peptide bond with a charged residue at this position is rarely cleaved, with the cleavage of the X-Lys bond by MMP-12 being an exception.72 The hydrophobic residues fit into the S1' specificity pocket, whose size and shape differ considerably among MMPs.39 In addition to the S1' pocket, other substrate contact sites (subsites) also participate in the substrate specificity of the enzyme.73
In some cases, noncatalytic domains influence the enzyme activity, particularly against large extended macromolecules of the ECM. For example, the fibronectin domains of MMP-2 and MMP-9 are important for its activity on type IV collagen, gelatin, and elastin.74,75 In collagenase 1 (MMP-1), the loop region just before the catalytic site helix (183RWTNNFREY) is essential for collagenolytic activity.76 Furthermore, the hemopexin domain and the hinge between the catalytic and the hemopexin domains also play key roles in collagenolysis (review by Overall77).
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Biological Activities Generated by MMP-Mediated Cleavage |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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A major function of MMPs is thought to be the removal of ECM in tissue resorption. However, the ECM is not simply an extracellular scaffold; it also acts as a reservoir of biologically active molecules, such as growth factors.2 Some ECM components can express cryptic biological functions on proteolysis. Hence, degradation of ECM components by MMPs can alter cellular behavior and phenotypes (Table 2). For example, the degradation of type I collagen by collagenase is associated with osteoclast activation,78 keratinocyte migration during reepitheliazation,79 and apoptosis of amnion epithelial cells before the onset of labor.80 MMP-2– and MT1-MMP–mediated cleavage of the
2 chain of laminin 5 exposes a cryptic promigratory site and promotes the migration of normal breast epithelial cells.81,82 Cleavage of CD44 by MT1-MMP is associated with cell migration.83 MMP-2 expressed in the Schwann cells of peripheral nerves degrades chondroitin sulfate proteoglycans and promotes neurite growth.84 Therefore, the function of MMPs is much more complex and subtle than straightforward demolition. Add to this the ever expanding number of non-ECM proteins that are MMP substrates and exert biological activities (for review, see McCawley and Matrisian85 and Sternlicht and Werb2), and the complexity of the role of MMPs in health and disease is evident.
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Endogenous MMP Inhibitors |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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TIMPs are specific inhibitors that bind MMPs in a 1:1 stoichiometry. Four TIMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) have been identified in vertebrates,5 and their expression is regulated during development and tissue remodeling. Under pathological conditions associated with unbalanced MMP activities, changes of TIMP levels are considered to be important because they directly affect the level of MMP activity.
TIMPs (21 to 29 kDa) have an N- and C-terminal domain of 
125 and 65 amino acids, respectively, with each containing three conserved disulfide bonds.86,87 The N-terminal domain folds as a separate unit and is capable of inhibiting MMPs.86 NMR first solved the structure of the N-terminal domain of TIMP-2 in 1994.88 The complete structure of TIMP-1 and of the inhibition mechanism was determined by X-ray crystallographic studies of the TIMP-1–MMP-3 complex,89 and soon after, that of the TIMP-2–MT1-MMP complex was determined.90 The overall shape of the TIMP molecule is like a wedge, which slots into the active-site cleft of an MMP in a manner similar to that of the substrate. Figure 5 shows the structures of the MT1-MMP catalytic domain, TIMP-2, and their interaction.90 The main sites of interaction of TIMP-2 with the catalytic domain are the N-terminal four residues and the CD-loop region adjacent to them. The N-terminal four residues bind in the catalytic site cleft, making backbone contacts similar to those of a substrate. Residues at 1 and 3 are strictly conserved cysteines that form disulfide bonds in the main body of the protein. Cys1 is instrumental in chelating the active-site zinc with its N-terminal -amino group and carbonyl group, thereby expelling the water molecule bound to the catalytic zinc.
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TIMPs inhibit all MMPs tested so far, except that TIMP-1 fails to inhibit MT1-MMP.91 However, the inhibitory property of TIMP-3 is different from the rest, inasmuch as it inhibits ADAM-17 (TACE),92 ADAM-10,93 ADAM-12,94 and the aggrecanases (ADAMTS-4 and ADAMTS-5).95 Kinetic studies have indicated that TIMP-3 is a better inhibitor for ADAM-17 and aggrecanases than for MMPs. Another unique feature of TIMP-3 is that it binds tightly to sulfated glycosaminoglycans.96 A possible role for TIMP-3 heart failure was observed with a reduction in the levels of TIMP-3, corresponding with adverse matrix remodeling in a cardiomyopathic hamster model and in the failing human heart.97
Application of TIMPs as a therapeutic tool for cardiovascular disease and cancer through gene therapy or direct protein application is still in an early phase of development (review by Baker et al98). However, there is a clear potential for the application of TIMPs as endogenous inhibitors, especially because the results of clinical trials with small molecule inhibitors have been disappointing.99 For example, adenoviral overexpression of TIMP-1 in a mouse model of atherosclerosis showed a reduction in the lesion.100 Local expression of TIMP-1 in a rat model of aneurysm prevented aneurism degradation and rupture.101 However, expressing wild-type TIMPs could have drawbacks because multiple MMPs may be inhibited, and in the case of TIMP-3, ADAMs and ADAMTSs may be inhibited as well. Probably the best route to success will be the development of engineered TIMPs with altered specificity, to allow targeting of specific proteinases.
Proteins such as plasma -macroglobulins are general endopeptidase inhibitors that inhibit most proteinases by trapping them within the macroglobulin after proteolysis of the bait region of the inhibitor.102 MMP-1 reacts with 2-macroglobulin more readily than with TIMP-1 in solution.103
Several other proteins have been reported to inhibit MMPs. Tissue factor pathway inhibitor-2 is a serine protease inhibitor that inhibits MMPs.104 A C-terminal fragment of the procollagen C-terminal proteinase enhancer protein has been shown to inhibit MMP-2.105 The secreted form, membrane-bound ß-amyloid precursor protein, has also been reported to inhibit MMP-2.106 RECK, a GPI-anchored glycoprotein that downregulates the levels of MMP-9 and active MMP-2 and suppresses angiogenic sprouting, leading to tumor cell-death,107 inhibits the proteolytic activity of MMP-2, MMP-9, and MT1-MMP.107,108 MMP-2, but not MMP-1, MMP-3, and MMP-9, is inhibited by chlorotoxin, a scorpion toxin that has anti-invasive effects on glioma cells.109 However, the mechanisms of MMP inhibition by these proteins are not known.
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Biological Functions of TIMPs |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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In addition to metalloproteinase-inhibiting activities, TIMPs have other biological functions. TIMP-1 and TIMP-2 have erythroid-potentiating activity110,111 and cell growth–promoting activities.112,113 Zhao et al114 found TIMP-1 in the nucleus of fibroblasts, and Ritter et al115 reported that TIMP-1 binds to the cell surface of MCF-7 breast carcinoma cells and subsequently translocates to the nucleus. During nephron morphogenesis, TIMP-2 participates in metanephric mesenchymal growth and in the morphogenesis of the ureteric bud, and the former activity is not due to MMP inhibition.116 Overexpression of TIMP-1, TIMP-2, and TIMP-3 reduces tumor growth (see Gomez et al4 for review). TIMP-2, but not TIMP-1, inhibits endothelial cell growth induced by basic fibroblast growth factor.117 These activities are also distinct from MMP inhibition, and their mechanism largely remains to be discovered.
TIMP-3 has proapoptotic activity, possibly through the stabilization of TNF- cell receptor 1, Fas, and TNF-related apoptosis, inducing ligand receptor-1, as shown for some tumor cells.118,119 On the other hand, TIMP-1 and TIMP-2 have antiapoptotic activity.120,121 TIMP-3 is associated with Sorsby’s fundus dystrophy, an autosomal-dominant disease that causes blindness due to macular degeneration.122 Mutations are all found in the C-terminal domain and include the substitution of a residue for a cysteine,123 a nonsense mutation,124 or a splice mutation,125 resulting in the deposition of the mutant TIMP-3 in Bruch’s membrane. Qi et al126 reported that the S156C mutant exhibited some reduction in MMP inhibitory activity, which was considered to promote angiogenesis. How this affects macular degeneration is not clear, but the S156C and S181C mutants form multiple complexes due to aberrant protein interaction and increased cellular adhesiveness, which may impinge on the turnover of Bruch’s membrane.127
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Conclusion and Future Prospects |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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MMPs are important components in many biological and pathological processes because of their ability to degrade ECM components. It has become clear that the ECM is not a mere scaffold for cells but that it also harbors cryptic biological functions that can be revealed on proteolysis. This puts a new light on the interplay between cells, the ECM, and its catabolism.
Considerable advancements have been made in the understanding of biochemical and structural aspects of MMPs, including their activation and catalytic mechanisms, substrate specificity, and the mechanism of inhibition by TIMPs. Nonetheless, there are important questions that remain outstanding. The structure of the proMMP-2–TIMP2 complex is a big step toward understanding how proMMP-2 assembles with TIMP-2 and MT1-MMP on the cell surface, but the precise molecular assembly in time and space during cell migration is yet to be investigated. In addition, although collagenase was the first member of the family to be discovered, the mechanism by which collagenases cleave triple-helical collagens is not understood. An explanation as to how TIMP-3, but not other structurally related TIMPs, inhibits metalloproteinases of the ADAM family awaits future structural studies.
Structural analyses have also led to the design of potent synthetic matrixin inhibitors, some of which have exhibited efficacy in animal models of cancer and arthritis, but unfortunately, clinical trials have shown no significant benefit. Such discrepancies may be due to the fact that the trials were conducted on patients with advanced stages of disease. Other possibilities are that the inhibitor concentration reached in vivo was insufficient to inhibit target enzymes in the tissue or that nontarget enzymes were inhibited. Currently, 23 MMPs and >30 ADAM metalloproteinases are known in humans, but their biological functions are not clearly understood. The design of specific inhibitors for these metalloproteinases is an important future challenge. Such inhibitors are useful not only for gaining insights into the biological roles of MMPs but also for the development of therapeutic interventions for diseases associated with unbalanced ECM degradation.
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Acknowledgments |
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This study was supported by The Wellcome Trust (grant 057508). We would like to thank Dr L. Troeberg for critical reading of the manuscript.
Received December 28, 2001; revision received March 25, 2003; accepted March 25, 2003.
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References |
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TopAbstractIntroductionMembers of the Matrixin...Three-Dimensional (3D)...Activation of ProMMPsSubstrate Specificity of MMPsBiological Activities Generated...Endogenous MMP InhibitorsBiological Functions of TIMPsConclusion and Future ProspectsReferences |
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M. Ouyang, S. Lu, X.-Y. Li, J. Xu, J. Seong, B. N. G. Giepmans, J. Y.-J. Shyy, S. J. Weiss, and Y. Wang Visualization of Polarized Membrane Type 1 Matrix Metalloproteinase Activity in Live Cells by Fluorescence Resonance Energy Transfer Imaging J. Biol. Chem., June 20, 2008; 283(25): 17740 - 17748. [Abstract] [Full Text] [PDF]
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 G. Cai, X. Zhang, Q. Hong, F. Shao, X. Shang, B. Fu, Z. Feng, H. Lin, J. Wang, S. Shi, et al. Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation Nephrol. Dial. Transplant., June 1, 2008; 23(6): 1861 - 1875. [Abstract] [Full Text] [PDF]
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M. Hasky-Negev, S. Simsa, A. Tong, O. Genina, and E. Monsonego Ornan Expression of matrix metalloproteinases during vascularization and ossification of normal and impaired avian growth plate J Anim Sci, June 1, 2008; 86(6): 1306 - 1315. [Abstract] [Full Text] [PDF]
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 J. A. Hoyland, C. Le Maitre, and A. J. Freemont Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc Rheumatology, June 1, 2008; 47(6): 809 - 814. [Abstract] [Full Text] [PDF]
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Y. Itoh, N. Ito, H. Nagase, and M. Seiki The Second Dimer Interface of MT1-MMP, the Transmembrane Domain, Is Essential for ProMMP-2 Activation on the Cell Surface J. Biol. Chem., May 9, 2008; 283(19): 13053 - 13062. [Abstract] [Full Text] [PDF]
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W. Sauter, A. Rosenberger, L. Beckmann, S. Kropp, K. Mittelstrass, M. Timofeeva, G. Wolke, A. Steinwachs, D. Scheiner, E. Meese, et al. Matrix Metalloproteinase 1 (MMP1) Is Associated with Early-Onset Lung Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1127 - 1135. [Abstract] [Full Text] [PDF]
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 C. Bendrik, J. Robertson, J. Gauldie, and C. Dabrosin Gene Transfer of Matrix Metalloproteinase-9 Induces Tumor Regression of Breast Cancer In vivo Cancer Res., May 1, 2008; 68(9): 3405 - 3412. [Abstract] [Full Text] [PDF]
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V. W.M. van Hinsbergh and P. Koolwijk Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead Cardiovasc Res, May 1, 2008; 78(2): 203 - 212. [Abstract] [Full Text] [PDF]
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 J D Raffetto and R A Khalil Mechanisms of varicose vein formation: valve dysfunction and wall dilation Phlebology, April 1, 2008; 23(2): 85 - 98. [Abstract] [Full Text] [PDF]
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A. Morikawa, N. Ohara, Q. Xu, K. Nakabayashi, D. A. DeManno, K. Chwalisz, S. Yoshida, and T. Maruo Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer Hum. Reprod., April 1, 2008; 23(4): 944 - 951. [Abstract] [Full Text] [PDF]
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M. Gerg, C. Kopitz, S. Schaten, A. Tschukes, C. Kahlert, M. Stangl, C. W. Hann von Weyhern, B. L.D.M. Brucher, D. R. Edwards, K. Brand, et al. Distinct Functionality of Tumor Cell-Derived Gelatinases during Formation of Liver Metastases Mol. Cancer Res., March 1, 2008; 6(3): 341 - 351. [Abstract] [Full Text] [PDF]
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 S. S. Fazel, L. Chen, D. Angoulvant, S.-H. Li, R. D. Weisel, A. Keating, and R.-K. Li Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury FASEB J, March 1, 2008; 22(3): 930 - 940. [Abstract] [Full Text] [PDF]
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 Q. Xu, N. Ohara, J. Liu, M. Amano, R. Sitruk-Ware, S. Yoshida, and T. Maruo Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells Mol. Hum. Reprod., March 1, 2008; 14(3): 181 - 191. [Abstract] [Full Text] [PDF]
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A. Baldan, A. V. Gomes, P. Ping, and P. A. Edwards Loss of ABCG1 Results in Chronic Pulmonary Inflammation J. Immunol., March 1, 2008; 180(5): 3560 - 3568. [Abstract] [Full Text] [PDF]
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 S. Perumal, O. Antipova, and J. P. R. O. Orgel Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis PNAS, February 26, 2008; 105(8): 2824 - 2829. [Abstract] [Full Text] [PDF]
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F. Schneider, G. K. Sukhova, M. Aikawa, J. Canner, N. Gerdes, S.-M. T. Tang, G.-P. Shi, S. S. Apte, and P. Libby Matrix Metalloproteinase-14 Deficiency in Bone Marrow-Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques Circulation, February 19, 2008; 117(7): 931 - 939. [Abstract] [Full Text] [PDF]
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Y. Y. Mahller, S. S. Vaikunth, M. C. Ripberger, W. H. Baird, Y. Saeki, J. A. Cancelas, T. M. Crombleholme, and T. P. Cripe Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors Cancer Res., February 15, 2008; 68(4): 1170 - 1179. [Abstract] [Full Text] [PDF]
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J.-J. Kim, J.-J. Li, K. S. Kim, S.-J. Kwak, D.-S. Jung, D.-R. Ryu, T.-H. Yoo, H. Y. Choi, S. H. Han, H. J. Kim, et al. High glucose decreases collagenase expression and increases TIMP expression in cultured human peritoneal mesothelial cells Nephrol. Dial. Transplant., February 1, 2008; 23(2): 534 - 541. [Abstract] [Full Text] [PDF]
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 G. Boden, W. Song, L. Pashko, and K. Kresge In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta Diabetes, February 1, 2008; 57(2): 476 - 483. [Abstract] [Full Text] [PDF]
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S. D'Alessio, G. Ferrari, K. Cinnante, W. Scheerer, A. C. Galloway, D. F. Roses, D. V. Rozanov, A. G. Remacle, E.-S. Oh, S. A. Shiryaev, et al. Tissue Inhibitor of Metalloproteinases-2 Binding to Membrane-type 1 Matrix Metalloproteinase Induces MAPK Activation and Cell Growth by a Non-proteolytic Mechanism J. Biol. Chem., January 4, 2008; 283(1): 87 - 99. [Abstract] [Full Text] [PDF]
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M. Plaisier, P. Koolwijk, F. Willems, F. M. Helmerhorst, and V. W.M. van Hinsbergh Pericellular-acting proteases in human first trimester decidua Mol. Hum. Reprod., January 1, 2008; 14(1): 41 - 51. [Abstract] [Full Text] [PDF]
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V. S. Golubkov, A. V. Chekanov, S. A. Shiryaev, A. E. Aleshin, B. I. Ratnikov, K. Gawlik, I. Radichev, K. Motamedchaboki, J. W. Smith, and A. Y. Strongin Proteolysis of the Membrane Type-1 Matrix Metalloproteinase Prodomain: IMPLICATIONS FOR A TWO-STEP PROTEOLYTIC PROCESSING AND ACTIVATION J. Biol. Chem., December 14, 2007; 282(50): 36283 - 36291. [Abstract] [Full Text] [PDF]
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Y. Wang, H. Rosen, D. K. Madtes, B. Shao, T. R. Martin, J. W. Heinecke, and X. Fu Myeloperoxidase Inactivates TIMP-1 by Oxidizing Its N-terminal Cysteine Residue: AN OXIDATIVE MECHANISM FOR REGULATING PROTEOLYSIS DURING INFLAMMATION J. Biol. Chem., November 2, 2007; 282(44): 31826 - 31834. [Abstract] [Full Text] [PDF]
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K. Sachidanandam, V. Portik-Dobos, A. K. Harris, J. R. Hutchinson, E. Muller, M. H. Johnson, and A. Ergul Evidence for Vasculoprotective Effects of ETB Receptors in Resistance Artery Remodeling in Diabetes Diabetes, November 1, 2007; 56(11): 2753 - 2758. [Abstract] [Full Text] [PDF]
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J. V. Cockle, N. Gopichandran, J. J. Walker, M. I. Levene, and N. M. Orsi Matrix Metalloproteinases and Their Tissue Inhibitors in Preterm Perinatal Complications Reproductive Sciences, October 1, 2007; 14(7): 629 - 645. [Abstract] [PDF]
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 M C Pustovrh, A Jawerbaum, V White, E Capobianco, R Higa, N Martinez, J J Lopez-Costa, and E Gonzalez The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats Reproduction, October 1, 2007; 134(4): 605 - 613. [Abstract] [Full Text] [PDF]
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 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
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J. Harslund, O. L. Nielsen, N. Brunner, and H. Offenberg Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1630 - R1639. [Abstract] [Full Text] [PDF]
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S. Munesue, Y. Yoshitomi, Y. Kusano, Y. Koyama, A. Nishiyama, H. Nakanishi, K. Miyazaki, T. Ishimaru, S. Miyaura, M. Okayama, et al. A Novel Function of Syndecan-2, Suppression of Matrix Metalloproteinase-2 Activation, Which Causes Suppression of Metastasis J. Biol. Chem., September 21, 2007; 282(38): 28164 - 28174. [Abstract] [Full Text] [PDF]
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B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]
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L. M. Hodgkinson, G. Duncan, L. Wang, C. J. Pennington, D. R. Edwards, and I. M. Wormstone MMP and TIMP Expression in Quiescent, Dividing, and Differentiating Human Lens Cells Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4192 - 4199. [Abstract] [Full Text] [PDF]
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 C. Muratori, A. Sistigu, E. Ruggiero, M. Falchi, I. Bacigalupo, C. Palladino, E. Toschi, and M. Federico Macrophages Transmit Human Immunodeficiency Virus Type 1 Products to CD4-Negative Cells: Involvement of Matrix Metalloproteinase 9 J. Virol., September 1, 2007; 81(17): 9078 - 9087. [Abstract] [Full Text] [PDF]
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 K. M. Thrailkill, R. C. Bunn, C. S. Moreau, G. E. Cockrell, P. M. Simpson, H. N. Coleman, J. P. Frindik, S. F. Kemp, and J. L. Fowlkes Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes Diabetes Care, September 1, 2007; 30(9): 2321 - 2326. [Abstract] [Full Text] [PDF]
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 B. Gogly, A. Naveau, B. Fournier, N. Reinald, E. Durand, C. Brasselet, B. Coulomb, and A. Lafont Preservation of Rabbit Aorta Elastin From Degradation by Gingival Fibroblasts in an Ex Vivo Model Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1984 - 1990. [Abstract] [Full Text] [PDF]
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S. Thalmann and C. A. Meier Local adipose tissue depots as cardiovascular risk factors Cardiovasc Res, September 1, 2007; 75(4): 690 - 701. [Abstract] [Full Text] [PDF]
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K. M. Heinemeier, J. L. Olesen, F. Haddad, H. Langberg, M. Kjaer, K. M. Baldwin, and P. Schjerling Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types J. Physiol., August 1, 2007; 582(3): 1303 - 1316. [Abstract] [Full Text] [PDF]
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L.-W. Qian, J. Xie, F. Ye, and S.-J. Gao Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Invasion of Primary Human Umbilical Vein Endothelial Cells by Inducing Matrix Metalloproteinases J. Virol., July 1, 2007; 81(13): 7001 - 7010. [Abstract] [Full Text] [PDF]
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R. K. Andrews, D. Karunakaran, E. E. Gardiner, and M. C. Berndt Platelet Receptor Proteolysis: A Mechanism for Downregulating Platelet Reactivity Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1511 - 1520. [Abstract] [Full Text] [PDF]
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M. H. Pillinger, N. Marjanovic, S.-Y. Kim, Y.-C. Lee, J. U. Scher, J. Roper, A. M. Abeles, P. I. Izmirly, M. Axelrod, M. Y. Pillinger, et al. Helicobacter pylori Stimulates Gastric Epithelial Cell MMP-1 Secretion via CagA-dependent and -independent ERK Activation J. Biol. Chem., June 29, 2007; 282(26): 18722 - 18731. [Abstract] [Full Text] [PDF]
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 S.-J. Chang, T.-Y. Wang, Y.-H. Lee, and C.-J. Tai Extracellular ATP activates nuclear translocation of ERK1/2 leading to the induction of matrix metalloproteinases expression in human endometrial stromal cells J. Endocrinol., June 1, 2007; 193(3): 393 - 404. [Abstract] [Full Text] [PDF]
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H. Bedair, T. T. Liu, J. L. Kaar, S. Badlani, A. J. Russell, Y. Li, and J. Huard Matrix metalloproteinase-1 therapy improves muscle healing J Appl Physiol, June 1, 2007; 102(6): 2338 - 2345. [Abstract] [Full Text] [PDF]
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J. Maleszewski, J. Lu, K. Fox-Talbot, and M. K. Halushka Robust Immunohistochemical Staining of Several Classes of Proteins in Tissues Subjected to Autolysis J. Histochem. Cytochem., June 1, 2007; 55(6): 597 - 606. [Abstract] [Full Text] [PDF]
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B. Marom, M. A. Rahat, N. Lahat, L. Weiss-Cerem, A. Kinarty, and H. Bitterman Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9 J. Leukoc. Biol., June 1, 2007; 81(6): 1466 - 1476. [Abstract] [Full Text] [PDF]
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S. Simsa, O. Genina, and E. M. Ornan Matrix metalloproteinase expression and localization in turkey (Meleagris gallopavo) during the endochondral ossification process J Anim Sci, June 1, 2007; 85(6): 1393 - 1401. [Abstract] [Full Text] [PDF]
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S. Simsa, A. Hasdai, H. Dan, and E. M. Ornan Differential regulation of MMPs and matrix assembly in chicken and turkey growth-plate chondrocytes Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2216 - R2224. [Abstract] [Full Text] [PDF]
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