Matrix Metalloproteinases and Synovial Joint Pathology

CHAPTER SEVEN

Matrix Metalloproteinases and Synovial Joint Pathology Charles J. Malemud1 Case Western Reserve School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, OH, United States 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Structure and Function(s) of MMPs 2.1 MMP-1 2.2 MMP-2 2.3 MMP-3 2.4 MMP-7 2.5 MMP-8 2.6 MMP-9 2.7 MMP-13 2.8 MT-MMP 3. MMPs and RA 4. MMPs and OA 5. MMPs and PsA 6. MMPs and Spondyloarthropathies 7. Three Mechanisms Regulating MMPs: Dysfunction in Synovial Joint Pathologies? 7.1 Tissue Inhibitor of Metalloproteinases 7.2 MMP-9/NGAL Complex 7.3 Signal Transduction Pathways 8. Conclusions and Future Perspective Acknowledgments References

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Abstract Matrix metalloproteinases (MMPs) are zinc-dependent enzymes. These enzymes play a critical role in the destruction of articular cartilage in rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and the spondyloarthropathies. MMP gene expression is upregulated in these synovial joint pathologies in response to elevated levels of proinflammatory cytokines and soluble mediators such as tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, IL-17, and interferon-γ. These molecules are capable of activating the mitogen-activated protein kinase and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways by binding the cytokine to their respective Progress in Molecular Biology and Translational Science, Volume 148 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2017.03.003

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2017 Elsevier Inc. All rights reserved.

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receptors on immune cells, macrophages, chondrocytes, synoviocytes, and osteocytes leading to increased synthesis of MMPs. Biologic drugs and/or small-molecule inhibitors designed to block cytokine to cytokine receptor interactions or to selectively inhibit JAKs have clinical efficacy in RA, PsA, and ankylosing spondylitis which correlated with a reduction in MMPs. Although there are currently no OA-selective drugs, it is likely that such a drug would have to reduce MMP gene expression to have clinical efficacy.

1. INTRODUCTION Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases. MMPs catalyze enzymatic reactions at neutral pH and play multiple roles in the turnover of macromolecular proteins and organ processing which is consistent with tissue remodeling.1 The MMP superfamily is comprised of several types of MMPs. These are the “classical” MMPs, MMP-1 (collagenase-1), MMP-8 (neutrophil collagenase), MMP-13 (collagenase-3), and gelatinases (MMP-2, 72 kDa gelatinase A; MMP-9, 92 kDa gelatinase B); the stromelysins (MMP-3, -10, and -11); the matrilysins (MMP-7/PUMP-1 and MMP-26); the membrane-type MMPs (MMP-14, -17, and -24/-25); the ADAMS (a disintegrin and metalloprotease) also known as adamlysins; and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif ).2-5 This chapter will focus on the role played by several of these MMPs which have been consistently implicated as participating in the pathogenesis and progression of diseases of synovial joints, including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and spondyloarthropathies, such as ankylosing spondylitis (AS). In addition to their role in several synovial joint pathologies, MMPs have been shown to regulate the activity of other proteases, growth factors, cytokines, as well as several mediators of inflammation.2

2. STRUCTURE AND FUNCTION(S) OF MMPs 2.1 MMP-1 The gene encoding MMP-1 is localized to chromosome 11q22.3. The proMMP-1 protein consists of 469 amino acids (Mw ¼ 54,007) and is comprised of a predomain, a prodomain, a catalytic domain, a linker region, as well as a hemopexin-like domain.6,7 The results of a study of synovitis showed that during the development of synovitis MMP-1 was activated by a mechanism

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involving plasminogen activator/plasminogen/prostromelysin, or alternatively, by a tryptases/pro-MMP-1 cascade.7 Thus, the activated form of MMP-1 cleaves Type I collagen at a single site in the helical domain which produces a ¼:¾ cleavage product, typical of mammalian collagenases. This degradation product can then be further processed by other matrixins most notably, the gelatinases (see later). The turnover of connective synovial joint collagens during skeletal maturation and development is also mainly regulated by the activity of MMP-1, aptly named, interstitial collagenase.8,9 Evidence for this effect of MMP-1 can be gleaned from classical studies performed by Edwards et al.10 who showed by immunochemical analysis that MMP-1 was localized to chondrocytes in zones that were distant from the joint line during embryologic development. From a functional perspective, MMP-1, also called fibroblast collagenase, is primarily implicated in mediating the degradation of Type I collagen,11 although Types II and III collagens are also substrates for MMP-1 and in certain cases, MMP-1 can cleave Types VII and X collagens.

2.2 MMP-2 MMP-2 is also known as 72 kDa gelatinase, gelatinase A, and Type IV collagenase. The MMP-2 gene is located on chromosome 16 at position 12.2 and produces a pro-MMP-2 protein which is comprised of 660 amino acids (Mw ¼ 73,882).12 At the structural level MMP-2 was shown to have three fibronectin Type II repeats in its catalytic site which is the basis for the molecular mechanism allowing for the binding of the enzyme to denatured Type IV collagen, Type V collagen, and elastin. Of note, the PEX domain of MMP-9 (see later) and MMP-2 was reported to contain both antiangiogenic and antitumor properties.13 This effect may be traced to the activity of the PEX domain as an inhibitor of cell migration and adhesion of cells to FGF2 and vitronectin. MMP-2 is considered the most ubiquitous metalloproteinase in this enzyme family in the sense that it is so intimately involved in many diverse cellular functions besides catalyzing the cleavage of extracellular matrix proteins. For example, MMP-2 regulates blood vessel formation and remodeling and also plays a role in tissue repair and regeneration as well as mediating the breakdown of tissues necessary for tumor invasion. MMP-2 is also a mediator of atherosclerotic plaque rupture.14

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However, in the context of synovial joint pathology, MMP-2 is a major participant in the degradation of extracellular matrix proteins as well as other cellular proteins. In that regard, MMP-2 degrades several nonmatrix proteins,15 including “Big” endothelial-1 and β-calcitonin gene-related peptide (β-type CGRP), the latter protein acting as an enhancer of blood vessel constriction. MMP-2 has also been shown to be involved in myocardial controlled cell death and appears to be essential for the myocardial oxidative stress response16,17 occurring most likely through its capacity to alter glycogen synthase kinase-3β (GSK3β) activity in that MMP-2 can cleave GSK3β in vitro. MMP-2 was also shown to mediate vascular regression.18

2.3 MMP-3 The gene encoding MMP-3 belongs to a group of MMP genes which cluster at chromosome 11q22.3. The pro-MMP-3 protein (also known as prostromelysin-1; Mw ¼ estimated at 54,000) is a product of many cell types. Pro-MMP-3 can be converted to its active form by sequential proteolysis of the pro-MMP-3 peptide through the plasminogen/plasmin cascade which avoids cleavage of the active-site cleft. Pro-MMP-3 activation can also occur by the action of MT-MMPs, whereas activated MMP-3 also can cleave proMMP-1, pro-MMP-7, and pro-MMP-9.19 MMP-3 degrades several ECM proteins among which elastin, fibronectin, laminin, Types III, IV, IX, and X collagens, as well as cartilage proteoglycans were shown to be the principal target substrates identified at the cell level.19

2.4 MMP-7 The MMP-7 gene was localized to chromosome 11q21–q22. The proMMP-7 protein (also known as matrilysin and PUMP-1 protease) has a Mw of 28,000 in the proform which is converted to a Mw of 19,000 after cleavage of the pro-MMP-7 prodomain.20 Pro-MMP-7 is generally activated either by the action of endoproteases or through the plasminogen/ plasmin cascade. However, MMP-7 differs from most members of the MMP protein family in that it is devoid of a conserved C-terminal protein region. MMP-7 can also activate other MMPs. For example, the activated form of MMP-7 or aminophenylmercuric acetate-activated pro-MMP-7 increased the activity of collagenase-1 and activated MMP-7 converted pro-MMP-2 to its active form.21 Proteoglycans, fibronectin, and elastin are several of the major ECM target substrates of MMP-7. However, MMP-7 was also shown to be involved in the processing of ECM proteins

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during normal embryologic development and reproduction, during the repair and remodeling of tissues and, in wound healing.

2.5 MMP-8 The MMP-8 gene as are other MMP genes was localized to chromosome 11q22.3. The pro-MMP-8 protein is, also known as neutrophil collagenase and collagenase-2, Mw ¼ 58,000.22 Although most MMP proteins are secreted in the proprotein form which are then generally activated by cleavage mediated by extracellular proteinases (see earlier), MMP-8 is stored in the secondary neutrophil granules where it is activated by autolytic cleavage.23 Although a principal function of MMP-8 is to degrade the cartilage proteoglycan, aggrecan,24 as well as Types I, II, and III collagens, MMP-8 has also been implicated in embryonic development, reproduction, and tissue remodeling and in the regulation of tumor cell adhesion and invasion, wherein MMP-8 was shown to be a potential tumor suppressor.25

2.6 MMP-9 MMP-9 is also known as 92 kDa Type IV collagenase, 92 kDa gelatinase, or gelatinase B. In the human genome, the MMP-9 gene encodes a pre-proenzyme consisting of 707 amino acids. Pre-pro-MMP-9 is a secreted MMP where the secreted form of MMP-9 is a zymogen. This proMMP-9 form consists of four evolutionary-conserved domains: a signal peptide, the amino-terminal propeptide, the zinc-binding catalytic domain containing three fibronectin Type II repeats, and the carboxy-terminal domain containing a hemopexin-like motif. Activation of pro-MMP-9 generally occurs through the action of the plasminogen/plasmin cascade but may also occur via activated MMP-3 which, in and of itself, is activated from pro-MMP-3 by plasmin. Thus, activated MMP-3 can cleave proMMP-9 resulting in the active form of MMP-9 (Mw ¼ 82,000)26 in the normal state. Activated MMP-9 is involved in physiological processes involving the degradation of ECM proteins which are pertinent to embryonic development and reproduction, cell migration, bone development, endochondral ossification, angiogenesis, neutrophil function, and wound repair.9 In pathological states, MMP-9 was shown to mediate cellular events related to metastasis25 and intracerebral hemorrhage. In synovial joint arthritis, MMP-9 is implicated in the final degradation steps leading to the loss of proteoglycans and collagen from articular cartilage.3-5

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2.7 MMP-13 The MMP-13 gene, also known as collagenase-3, is localized to chromosome 11q22.3 similar to other MMP genes. As such, MMP-13 is a secreted MMP in the form of a zymogen. The proform of MMP-13 consists of 471 amino acids (Mw ¼ 53,820). Cleavage of the proform of MMP-13 results in its activation. The activated form MMP-13 is comprised of a catalytic domain and a hemopexin-like domain. Importantly, the hemopexin-like domain dominates the degradation properties of MMP-13. Although the catalytic domain of MMP-13 by itself can also degrade collagen but is not as efficient in doing so as the hemopexin-like domain. MMP-13 is a particularly critical MMP during skeletal development and long-bone maturation27 because MMP-13-mediated degradation of the preexisting ECM proteins was shown to be a necessary step prior to neoangiogenesis and mineralization.9 Of note, the overproduction of MMP-13 is significant in various pathological states where MMP-13 was shown to degrade collagens, aggrecan, fibronectin, and tenascin as well as other ECM proteins, making MMP-13 critical for the progression of human carcinoma,28 RA and OA.1

2.8 MT-MMP MT-MMP is also known as MT1-MMP and MMP-14. The MMP-14 gene is localized to chromosome 14q11.2. The protein encoded by the MMP-14 gene consists of 582 amino acids (Mw ¼ 65,894). Members of the MT-MMP gene family are comprised of a transmembrane domain, indicating that these MMPs are preferentially localized to the cell surface rather than being a secretory MMP as is the case with other MMP family members. The MT-MMP proteins are known to be activators of MMP zymogens.29 For example, MMP-14 can activate pro-MMP-230 and may therefore play a role in tumor invasion31 and in synovial joint pathologies where activation of MMP-2 is critical. MT1-MMP may also be important for cytoskeletal reorganization through its capacity to cleave membrane PTK7 pseudokinase. Studies were performed with N-ethyl-N-nitrosourea-induced (chuzoi) mutant mice which had severe birth defects associated with lower levels of PTK7. This finding suggested that PTK7 was critical for shaping the body plan during embryonic development.32 In addition to its role as an MMP zymogen activator, MT1-MMP was also shown to be effective in degrading ECM proteins which can provide a mechanism allowing cells to migrate and to remove cell surface molecules which inhibit migratory signals as well as activating extracellular signal-regulated protein kinase (ERK) thus promoting a mechanism required for cell migration.32

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3. MMPs AND RA RA is a systemic, chronically progressive musculoskeletal disease that principally affects the integrity of synovial joints.33 Although no precise etiologic agent has been implicated in the pathogenesis of RA, a better understanding of how genetic34-37 and environmental38-40 factors initiate inflammatory responses in RA has been developed which significantly involve altered innate and adaptive immune responses.41 For example, a major advance in our understanding of RA pathogenesis arose when it was discovered that B cells which produce anticyclic citrullinated antibodies do so in some individuals well prior to the time when the signs and symptoms of RA become clinically relevant.42-44 At the pathophysiological level, RA progression is associated with significantly elevated levels of proinflammatory cytokines, most prominently, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-7, IL-8, IL-17, interferon-γ. These cytokines activate signal transduction pathways that appear to regulate MMP gene expression.38-40 For example, IL-6 primarily activates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by binding IL-6 to the IL-6/gp130/ IL-6-receptor, or alternatively, to membrane-bound and/or soluble IL-6 receptor.38-41 In that regard, one of the main downstream cellular events in RA is regulated by phosphorylation of STAT proteins in response to the increased levels of proinflammatory cytokines.42 However, another component of this response is the upregulation of MMP gene expression.1 Recently, we showed that recombinant human (rh)-IL-6 significantly increased the production of MMP-9 by the C-28/I2 line of immortalized human chondrocytes.43 We also showed that incubation of human chondrocytes derived from osteoarthritic knee cartilage with rhTNF-α resulted in the selective phosphorylation of the STAT3 protein,44 indicating that, at least in the milieu of cultured human chondrocytes, rhTNF-α can activate the JAK/STAT pathway in addition to its more conventional signaling target, the mitogen-activated protein kinase pathway.41 More importantly, we found that tocilizumab, a monoclonal antibody which neutralizes the interaction between IL-6 and its receptor, significantly reduced MMP-9 production by C-28/I2 chondrocytes as well as in T/C28a2, another immortalized human chondrocyte line.45 Of note, the combination of rhIL-6 and soluble IL-6 receptor also reduced MMP-9 production by the C-28/I2 human chondrocyte line,46 suggesting that neutralization of JAK/STAT signaling was coupled to upregulation of the MMP-9 gene. Taken together, these

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in vitro results indicated that the significantly elevated level of IL-6 found in the sera and synovial fluid of RA patients is likely to be responsible for the upregulation of the MMP-9 gene as well as other MMPs that are relevant to RA as well as the degradation of cartilage ECM proteins which is characteristic of RA pathology. The results of numerous experimental and clinical studies showed that, in addition to the role played in RA by MMP-9,47 other MMPs, specifically, MMP-1,48-51 MMP-2,52 MMP-3,50,51,53 MMP-8,54,55 MT1-MMP,56,57 MMP-10/-12,58 and MMP-1359,60 mediate various aspects of human RA pathology61 as well as experimentally induced arthritis in rodent models of RA.59 The cellular events for which MMPs have been associated with RA are (1) reduced apoptosis by inflammatory neutrophils,55,62 (2) synoviocyte migration and invasion,47,57 (3) activity of receptor activator of nuclear factor-κB ligand (RANKL)/RANK binding and retinoid-related orphan receptor levels,53 (4) cadherin 11 receptor engagement,50 (5) synoviocyteinitiated angiogenic responses,59 and (6) severe and destructive synovitis.60

4. MMPs AND OA Primary OA is characterized by altered chondrocyte metabolism wherein catabolic events override anabolism.63 In that respect, those chondrocytes located in the superficial zone of articular cartilage are the most significantly altered in early OA. These chondrocytes produce most of the MMPs which are responsible for the degradation and loss of the pericellular, and interterritorial proteins of the cartilage extracellular matrix. Although the ADAMTS class of enzymes have clearly been implicated in OA progression,64-66 evidence for a significant role of MMP gene upregulation is persuasive and imparts a major role for this enzyme class in the destruction of articular cartilage and resultant joint failure.67,68 Thus, the elevated levels of MMPs, including MMP-169 MMP-2,70,71 MMP3,72,73 MMP-9,69,74 MMP-13,70,75,76 and MT1-MMP63 in OA sera and synovial fluid, are consistent with their role in orchestrating cartilage ECM protein degradation.77 By contrast, MMP-8 appears to play only a minor role in OA in the degradation of collagen.78 Of note, several of the proinflammatory cytokines that have been identified as participating in RA progression, such as TNF-α, IL-1β, IL-6, have also been found at elevated levels in the sera and synovial fluid of OA patients.77 This finding suggested that a “final” common pathway is likely to exist between RA and OA.77,79

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5. MMPs AND PsA PsA is an autoimmune-mediated chronic inflammatory disease of synovial joints,80 although the inflamed synovium from patients with PsA possessed significantly different histopathologic features compared to synovial tissue from patients with RA.81 As was found in RA, IL-17,80,82 TNF-α,80 and IL-2283 are also prominently involved in the pathogenesis and progression of PsA. This is supported by the clinical efficacy of TNF blockade and the administration of secukinumab, a novel fully humanized anti-IL-17 IgG1κ monoclonal antibody in the therapy of PsA.80 The synovial fluid of PsA patients was also found to be rich in IL-22,83 suggesting an additional future target for therapeutic intervention in PsA. As might be expected from the elevated presence of TNF-α and IL-17, the sera from patients with PsA contained elevated levels of MMP-2 and -984 wherein MMP-2 was detected as the zymogen form of MMP-2, while MMP-9 was present in both latent and active form. Kane et al.85 also showed the presence of elevated levels of MMP-1 and -3 mRNA in both PsA and RA synovium, despite the reduced evidence of bone erosion in the PsA joints. The level of serum MMP-9 also correlated with serum levels of high-sensitivity C-reactive protein (hs-CRP), another biomarker of inflammation.86 Of note, therapy of PsA with the TNF blocker, infliximab, resulted in diminished levels of MMP-9, as well as TNF-α and E-selectin which was correlated with an improvement in the psoriatic arthritis severity index.87 This relationship also appeared to hold as a measure of clinical response to treatment of PsA patients with etanercept, or golimumab, or adalimumab, or infliximab as determined by the reduction in serum MMP-3.88 Importantly, reduced levels of MMP-9 were also associated with lower TNF-α levels, suggesting a strong relationship between this proinflammatory cytokine and MMP-9 production. Equally as critical, Hitchon et al.89 had immunolocalized MMP-2 to PsA synovial membrane as well as to the synovial lining layer where anti-MMP-2 staining was similar between PsA and RA. However, PsA synovial membrane contained increased gelatinase activity as determined by zymography. Interestingly, compared to PsA synovial membrane, psoriatic skin lesions had lower levels of MT1-MMP and MT2-MMP. When all of this evidence is considered together, it can be concluded that PsA is characterized by elevated levels of MMP-2, -3, and -9.

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6. MMPs AND SPONDYLOARTHROPATHIES The terms spondyloarthropathy or spondyloarthrosis refer to any musculoskeletal disease that preferentially affects the vertebral column.90 In that respect, spondyloarthropathy accompanied by inflammation is commonly referred to as AS. The classic genetic marker for predicting the development of AS is a positive genetic test for the HLA-B27 allele.91 Thus, it was reported that 92% of Caucasians who were positive for the HLA-B27 allele showed clinical evidence of AS, which was reduced to 50% in testing for HLA-B27 in African-Americans. Importantly, individuals who can show clinical or X-ray evidence of vertebral column involvement from RA or OA are commonly referred to as not having a diagnosis of AS but rather a diagnosis of seronegative spondyloarthropathy. Important biomarkers for evidence of inflammation associated with AS and axial spondyloarthropathy include CRP, an elevated erythrocyte sedimentation rate (ESR), and elevated MMPs especially, with particular reference to MMP-3.91 In fact, several studies92-94 showed evidence that AS was correlated with high levels of MMP-3 wherein high levels of serum MMP-3 appeared to predict the degree of structural damage in these patients.95 AS patients have also been shown to have elevated MMP-1 compared to individuals with degenerative disc disease,96 although in this study both patients with AS and degenerative disc disease showed similar levels of MMP-3. Since several studies have also shown a relationship between elevated levels of TNF-α and MMP-3, Arends et al.97 determined the extent to which AS patients responded clinically to therapy with etanercept and whether the clinical response was associated with changes in serum MMP-3. The results of this study showed that clinical responsiveness to etanercept correlated with a lowering of serum MMP-3, although the study also concluded that MMP-3 levels had little routine utility in clinical practice for assessing the response of AS patients to TNF blockade. Another earlier study employing infliximab for the therapy of AS showed that the clinical response to infliximab measured by MRI did not correlate with reduced MMP-1 and -3, but significant correlations were found between infliximab therapy and changes in the Bath ankylosing spondylitis disease activity index (BASDAI), an indicator of clinical activity in AS together with ESR, CRP, and MMP-3.98 However, Sun et al.99 showed that the level of activated MMP-3 in the serum of AS patients correlated with CRP and ESR, once again suggesting a strong relationship between serum MMP-3 and these two biomarkers of inflammation. Mattey et al.100 also showed that

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the changes in BASDAI were between BASDAI and a group of clustered biomarkers consisting of MMP-8, MMP-9, hepatocyte growth factor, the chemokine, CXCL8, whereas no association between BASDAI and CRP was demonstrated. However, a hierarchical clustering analysis showed that high levels of MMPs correlated with elevated CRP, BASDAI, and the Bath AS functional index. More recently a complete analysis of therapy of AS with the anti-IL-17 monoclonal antibody, secukinumab, showed evidence of clinical efficacy.101 Finally, an in vitro study of synovial tissue from patients with AS revealed an elevated expression of TNF-α, vascular endothelial growth factor, and MMP-3 mRNA which were positively correlated with synovial tissue samples acquired on the basis of high or lower BASDAI.102 Although there are several discrepancies between the results of various clinical studies in AS patients with respect to biomarkers of inflammation, it can be surmised from considering them together that elevated levels of serum MMPs best correlate with clinical activity as determined by BASDAI.

7. THREE MECHANISMS REGULATING MMPs: DYSFUNCTION IN SYNOVIAL JOINT PATHOLOGIES? 7.1 Tissue Inhibitor of Metalloproteinases Tissue inhibitor of metalloproteinases (TIMPs) are the principal endogenous inhibitors of MMPs. The inhibition of MMPs follows a mechanism whereby a family of TIMP proteins, namely TIMP-1, -2, -3, -4, binds to various forms of MMPs103 and also to ADAMTS4104 which regulates MMP and ADAMTS activity. Of note, the 2-domain TIMPs are of relatively small molecular size, can inhibit activated MMPs as well as the conversion of pro-MMPs to activated MMPs, and can regulate a variety of other cellular functions which may or may not directly involve MMPs.105 However, in the present context the results of several although not all studies have clearly indicated that TIMP activity was low and, even if present was essentially inefficient in regulating MMP activity in OA5,76,106,107 and RA,108 where in RA, the concentration of TIMP-1 and -2 was higher in synovial fluid than in sera.84 Of interest Kane et al.85 reported that both RA and PsA had similar levels of TIMP-1 mRNA expression, despite the greater degree of erosive disease in RA. However, no differences were found in TIMP-1 levels when synovial tissue in RA and PsA which was collected from the cartilage–pannus interface was compared to synovium from areas distal to pannus although van der Laan et al.109 had previously found that TIMP-3 was overexpressed in the invasive “front” of RA pannus thus making

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TIMP-3 a somewhat unexpected target in RA for therapeutic intervention.110 In another study, an analysis of TIMP-1 and -2 revealed that these TIMPs were elevated in the sera of RA patients compared to OA patients.111 This finding suggested that the low levels of TIMP which are characteristic of OA may also reflect various elements of OA disease progression rather than merely the extent of cartilage erosions typically found in both types of arthritis. Importantly, from a therapeutic perspective, an attempt to modify MMP activity in OA with exogenous TIMPs proved to have little, if any, clinical efficacy.112

7.2 MMP-9/NGAL Complex Meszaros and Malemud63 reviewed another potential mechanism for regulating MMP activity specifically focusing on the formation of a complex between MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Gupta et al.113 had previously shown that MMP-9 existed in a complex with NGAL in synovial fluid from OA patients that were undergoing knee replacement surgery, indicative of severe late-stage OA. Furthermore, Gupta et al.113 found that the MMP-9/NGAL complex prevented MMP-9 from undergoing autodegradation. Furthermore, the MMP9/NGAL complex was highly active in its capacity to degrade cartilage proteoglycan in vitro. Of note, dissolution of the MMP-9/NGAL complex using antibody-specific immunoprecipitation resulted in the release of MMP-9 from the MMP-9/NGAL complex and the loss of MMP-9 activity. We had also previously shown that NGAL was produced by human chondrocytes in vitro.114 This finding suggested that NGAL production was likely to have occurred in concert with MMP-9 synthesis in these chondrocytes. More recently, we showed that two lines of immortalized human juvenile chondrocytes synthesized MMP-9 and NGAL.44,46 Thus, incubating the C-28/I2 chondrocyte line with rhIL-6 increased MMP-9 production and the combination of rhIL-6 and tocilizumab, a monoclonal antibody which neutralizes the binding of IL-6 to its receptor or the combination of rhIL-6 and soluble IL-6 receptor inhibited MMP-9 production. However, incubation of C-28/I2 chondrocytes with rhIL-6 or rhIL-6 and tocilizumab did not increase NGAL production, suggesting that MMP-9 and NGAL synthesis could be uncoupled in cultured human chondrocytes.

7.3 Signal Transduction Pathways Activation of the MAPK and JAK/STAT signaling pathways by proinflammatory cytokines, such as TNF-α, IL-1β and IL-6, IL-17, can

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result in MMP gene upregulation.115-117 Because we and others have previously shown that rhTNF-α or rhIL-6 activated more than one signaling pathway, namely MAPK and JAK/STAT signaling, we and others have proposed that the progression of synovial joint pathology is likely to be dependent on a continuous activation of these signaling pathways by many of the proinflammatory cytokines involved in arthritis.118,119 In that regard, various components of these signal transduction pathways have been explored as targets for reducing MMP gene expression through inhibition of the action of these cytokines. These have included TNF and IL-6 receptor blockade,41,120,121 employing small-molecule inhibitors (SMIs), such as the JAK3-selective SMI, tofacitinib,122 the use of experimentally induced Raf kinase inhibitor protein silencing RNA,123 or SMIs directed against p38 kinase and ERKp44/p42 SMI.124 Drug-induced inhibition of MAPK and JAK/STAT pathway activation has generally resulted in reduced MMP production. Therefore, it should be informative going forward to determine the effect of other drugs in development for RA on MMP levels in sera and synovial fluid to see if improvements in clinical responses to these drugs correlate with reduced MMP production.

8. CONCLUSIONS AND FUTURE PERSPECTIVE MMPs and the ADAMTS class of enzymes play crucial roles in the final disposition of synovial joint pathology such as OA, RA, PsA, and AS. Although there are a few exceptions, the types of MMPs found to be active in these joint pathologies (Fig. 1) suggest that a considerable overlap exists in the final “common” MMP-mediated pathways that contribute to joint destruction in these conditions. For example, the loss of proteoglycans, collagens, and ECM accessory proteins from articular cartilage produced by the action of these enzymes permanently alters the biomechanical properties of the tissue that ultimately results in synovial joint failure. Although research continues to search for potent chemical MMP inhibitors, such as W0201215158, an experimental aromatic scaffold based on isoxazolines, which was reported to inhibit MMP-13,125 it is likely that a more fortuitous approach toward reducing the activity of MMPs and ADAMTS will be based on the further development of SMIs that suppress the continuous activation of signaling pathways which are activated in arthritis by proinflammatory cytokines. Thus, the development and successful use of tofacitinib, a selective inhibitor of JAK3, in the therapy of RA should also be analyzed for its capacity to blunt MMP and ADAMTS gene expression. Another approach which could be considered to modify the activity of

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OA MMP-1 MMP-2 MMP-3 MMP-9 MMP-13 MT-MMP

RA MMP-1 MMP-2 MMP-3 MMP-8/-9 MT1-MMP MMP-10/-12 MMP-13

PsA/AS MMP-2 MMP-9 MMP-1 MMP-3

Fig. 1 Three-circle Venn diagram showing the degree of distinct and overlapping MMP types in OA, RA, PsA, and AS. This three-circle Venn diagram shows that although there are distinct MMP patterns in each of the synovial joint pathologies, OA, RA, PsA, and AS, there is also considerable overlap in the types of MMPs among these four synovial joint pathologies. A notable exception of MMP-8 which was reported to play a role in patients with RA54,55 but only a minor role in OA.78 In addition, MMP-8 was not reported in patients with PsA or AS. In contrast, MMP-10/-1258 was found in RA patients but was not reportedly found in OA, whereas MMP-13 and MT1-MMP were reported to be present in patients with RA56,57 or OA,63 but not in patients with PsA or AS.

MMPs should exploit the enzyme–protein interactions63 that maintain certain MMPs, such as MMP-9 in an activated state through the formation of a complex of MMP-9 with NGAL.113,114 Thus, experimental studies employing silencing RNA technology should be explored to determine the extent to which suppression of NGAL gene expression would lead to the loss of MMP-9 activity. If this approach proved to have utility, it would then be prudent to search for additional enzyme–protein interactions which permit other MMPs to remain active in synovial joint pathologies.

ACKNOWLEDGMENTS I wish to acknowledge the many collaborators, beginning in 1977, who have worked with me over the past 40 years, to probe the role played by MMPs in chondrocyte metabolism and arthritis [see, for example, a review of our published studies from 1977 to 81 in Ref. 126]. More recently, the experimental studies cited in Refs. 44–46, 113, and 114 were supported by grants from NCCAM (R01-AT-002258), NIAMS (R01-AR-48782), The CWRU Visual Sciences Research Core Center Grant (P30-EY-11373), NICHD (R01-HD-061819),

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and Investigator-initiated project grants from Takeda Pharmaceuticals of North America and Genentech/Roche Group. I also wish to thank Peyvand Amini, MD for support in rendering Fig. 1.

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