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Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo

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Jean Gaffney 1, 2, † , Inna Solomonov 1, † , Eldar Zehorai 1 and Irit Sagi 1 1 - Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel 2 - Department of Natural Sciences, Baruch College, New York, NY, USA

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Abstract

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The matrix metalloproteinases (MMPs) play a crucial role in irreversible remodeling of the extracellular matrix (ECM) in normal homeostasis and pathological states. Accumulating data from various studies strongly suggest that MMPs are tightly regulated, starting from the level of gene expression all the way to zymogen activation and endogenous inhibition, with each level controlled by multiple factors. Recent in vivo findings indicate that cell–ECM and cell–cell interactions, as well as ECM bio-active products, contribute an additional layer of regulation at all levels, indicating that individual MMP expression and activity in vivo are highly coordinated and tissue specific processes.

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Correspondence to : http://dx.doi.org/10.1016/j.matbio.2015.01.012 Edited by W.C. Parks and S. Apte

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© 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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The matrix metalloproteinases (MMPs) are enzymes known for their remarkable ability to irreversibly degrade complex substrates in the extracellular matrix (ECM), process and cleave chemokines, and shed cell membrane proteins during homeostatic processes and in pathological states [1–3]. Despite their high structural homology at their catalytic domain [4], MMPs demonstrate indistinguishable substrate specificity in vitro [5–7]. The fact that over two dozen of these proteins have been identified in vivo strengthens the notion that each MMP serves unique roles within tissues. Many of the MMPs appear to be tissue specific and are expressed at distinct concentration during homeostasis, a feature difficult to reproduce in in vitro experiments, which often produce artificial conditions where the system is saturated with the enzyme, leading to non-specific binding and cleavage of substrates, which would not necessarily occur in vivo. Here, we address the tight regulation of these enzymes within the tissue and make a case for the selectivity of each MMP for its native substrates in vivo. The data collected in the recent decades strongly suggest that MMP expression and activity in vivo are subjected to tight regulation at various levels, from

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gene expression to zymogen activation and endogenous inhibition. This intricate regulation is essential for maintaining tissue homeostasis. Expression of most MMPs is controlled at the level of transcription [8–10], except in the notable cases of the storage of MMP-9 and MMP-8 in neurophils, though the factors, governing the expression of specific MMPs in different cells and tissues have yet to be fully defined. However, the role of several external factors impacting transcriptional activation of MMPs has been shown. These factors include ECM functional molecules, such as inflammatory cytokines, hormones and growth factors, such as transforming growth factor beta (TGFβ), epidermal growth factor receptor (EGFR), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [11–21]. Several studies have reported that prostaglandin E2 (PGE2), a bioactive lipid molecule, up regulates MMP-1, MMP-2, MMP-9, and MT1-MMP gene transcription [22–25]. Another factor, PGE2, was found to down regulate MMP-13 in TNF-α-enhanced fibroblasts [19] and MMP-1 and MMP-13 in IL-1βinduced chondrocytes [26,27]. It was also shown that oxidized low-density lipoprotein (LDL) regulates MMP-9 expression in human monocyte-derived

0022-2836/© 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Matrix Biol (2015) xx, xxx–xxx Please cite this article as: Gaffney Jean, et al, Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo, Matrix Biol (2015), http://dx.doi.org/10.1016/j.matbio.2015.01.012

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thereby, preventing catalysis [87]. Activation may alternatively occur by destabilizing the propeptide domain conformation, resulting in loss of cysteine switch–zinc interaction [7,88,89]. Importantly, the activation of MMPs in vivo may be adjusted chemically, i.e., hypoxia and NO were shown to be activators of proMMP-2 and pro-MMP-9, respectively [36,90]. The versatility of MMP possible activation mechanisms and the observed nuances of enzyme kinetics within a specific tissue provide further proof that the evolution of this class of enzymes has led to each member requiring specific conditions for its activation and, correspondently, to define substrate specificity in each tissue. Alongside MMP activation mechanisms are those responsible for MMP inhibition. Prominent among these inhibitors are the TIMP family of proteins, which are secreted by various cells and are able to selectively target individual MMPs by inserting a conserved anchor into the active site of the target MMP and chelate the catalytic zinc ion [91]. In a similar manner to MMPs, TIMPs' expression is too regulated by diverse ECM factors [58,92–95]. It is known that TIMPs inhibit MMPs mainly via their N-domains [96], causing a decrease in the flexibility of the enzymes' binding interfaces [97]. TIMPs exhibit high sequence homology with comparable affinities to most MMPs in vitro. In the case of TIMP-2, computational results reveal that its binding interface with its target MMPs is not optimal [98]. Thus, the elucidation of TIMP selectivity to each protease as well as the relevance of these computational findings in vivo is yet to be determined. An additional point to be considered is that in contrast to previous suggestions, recent data highlight the in vivo heterogeneity of MMP-2 and MMP-9 [99] and the differential regulation of MMP-9 trimers by TIMP-1 in contrast to the monomers [100]. Since the tissues of different organs have specific ECM composition and three dimensional structures that are constantly being remodeled, it is reasonable to suggest that the resident cells of each tissue have to express remodeling enzymes specific for the ECM proteins of the tissue. For example, the basement membranes and submucosal structures contain fibronectin [101], which affects the expression and activity of MMP-9 in human vein endothelial cells [102]. Furthermore, T-lymphocyte migration into tissues occurs through their adherence to fibronectin, which induces the production of activated MMP-9 and MMP-2, as well as coordinated expression of MT1-MMP [103]. Similarly, the activation of proMMP-2 concomitantly with MT1-MMP by fibronectin was observed in fibrosarcoma cells [104], demonstrating that the activation of MMP-2 is regulated by the nature of the ECM. In addition, the fibronectin fragments, generated by HTRA1 secreted serine protease, cause a significant increase in MMP expression [105].

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macrophages and MMP1 in human vascular endothelial cells [28–30]. In addition, MMP-1, MMP-2, MMP-9 and MMP-13 gene expression was found to be up regulated by hyperglycemia [31–34], where it may work synergistically with other ECM molecules, such as IL-6 [35]. In contrast, in human endothelial cells, hypoxia/reoxygenation conditions were found to increase or decrease the expression level of MMP-2, depending on the duration of exposure to hypoxia [36]. This intricate transcriptional regulation of MMPs becomes even more complicated when taking into account the impact of promoter polymorphisms, epigenetic regulation mechanisms [9,37–40], and post-transcriptional processes. The latter includes mRNA stability, protein translational efficiency, and microRNA-based mechanisms [41–44]. Remarkably, cell–ECM (structural and functional proteins), and cell–cell interactions also induce the gene expression of MMPs [45–54]. Studies have revealed that, often, ECM molecules affect both transcriptional and post-transcriptional mechanisms to modify MMP expression. Of note, TGFβ1 can either increase or inhibit MMP levels, depending on cell type [55–58]. Thus, the data published in recent years strongly suggests that MMP gene expression is determined by different external and ECM factors and may be cell and ECM specific. The next level in MMP control is zymogen activation, which may be achieved intracellularly, at the cell surface and within the extracellular space (Fig. 1). Intracellular activation, for example, occurs in MMP-11 and MT1-MMP via proteolytic activation by cellular endoproteases [59–61], via oxidative stress in the case of latent collagenases [62,63] and via phosphorylation in the case of MMP-2 [64,65]. It is important to note that the data collected regarding non-specific MMP intracellular activation comes mainly from in vitro experiments; whether or not this is the case in vivo remains an open question. At the cell surface, the activation of MMP-2 occurs mainly via various MT-MMPs, by different mechanisms [66–68]. One of the mechanisms is the two-step activation of proMMP-2 by MT1-MMP: first, a complex comprising proMMP-2-MT1-MMP and tissue inhibitor of metalloproteinases 2 (TIMP-2) is formed. Next, proMMP-2 is cleaved by MT1-MMP to be activated [69]. This process is mediated by the binding of the hemopexin domain of proMMP-2 to integrin [70]. In contrast, the activation of proMMP-2 by MT2-MMP occurs via a TIMP-2-independent mechanism [71]. At the extracellular environment, the proteolytic activation of MMPs is regulated by various classes of enzymes, such as fibrinolytic protease plasmin, serine protease tissue kallikrein, thrombin, trypsin and other MMPs [72–86]. The most known mechanism of MMP zymogen activation results in the release of the active MMP following proteolysis of the pro-domain, responsible for shielding the catalytic machinery and,

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Multilevel regulation of matrix metalloproteinases

Please cite this article as: Gaffney Jean, et al, Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo, Matrix Biol (2015), http://dx.doi.org/10.1016/j.matbio.2015.01.012

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Multilevel regulation of matrix metalloproteinases

Please cite this article as: Gaffney Jean, et al, Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo, Matrix Biol (2015), http://dx.doi.org/10.1016/j.matbio.2015.01.012

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Fig. 1. Schematic representation of the various modes of MMPs zymogen activation. Intracellular activation may occur via proteolytic activation by cellular endoproteases, oxidative stress and phosphorylation. In the case MMP-2, its activation can take place at the cell surface by various MT-MMPs through different mechanisms. One such is the two-step activation of proMMP-2 by MT1-MMP, as illustrated. Initially, a complex comprising proMMP-2-MT1-MMP and TIMP-2 is formed, allowing the cleavage of proMMP-2 by MT1-MMP and to its activation. At the extracellular environment, the proteolytic activation of MMPs may be regulated by various factors as indicated.

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Multilevel regulation of matrix metalloproteinases

Fig. 2. Schematic representation of multifactorial MMP regulation at the level of gene expression, zymogen activation and endogenous inhibition.

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[118,119]. In addition, the activity of MMPs in body fluids and blood is also regulated by other factors, such as reactive oxygen species or coagulation factors [120,121]. Thus, recent evidence suggests that inhibition of MMP activity is tightly regulated, highlighting that the complex scenario that occurs in vivo remains challenging. Unfortunately, little knowledge exists regarding the molecular mechanisms by which active ECM bio-products activate or inhibit MMPs. Over the last twenty years, as a result of the move from in vitro experiments to in vivo systems, our understanding of the specific roles of each MMP in its native environment has grown immensely and has been characterized in greater detail [122]. The development of advanced degradomics in the cellular context, in particular, has significantly clarified the role of specific MMPs. It has enabled the identification of new biological substrates (including intracellular ones [123]) for MT1-MMP, MT6-MMP [124,125] and the closely related MMPs MMP-2 and MMP-9 [126]. In addition, the development of protein engineering with imaging probes designed to inhibit and image specific MMPs to studies related to selective MMP functions in vivo [127]. This review outlines the current knowledge of the tight multilevel regulation of MMPs essential for tissue homeostasis (Fig. 2). Although many factors regulating MMPs activation have been identified (both external and ECM related), the complex, but yet highly specific and tightly regulated, combinatory network is yet to be fully elucidated. Since the data strongly suggest that MMP regulation occurs from the level of transcription expression to that of zymogen activation and endogenous inhibition, identifying the MMP regulatory factors at every level within each tissue will help develop new selective therapeutic agents against various diseases.

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The fact that active bio-products of ECM proteins also regulate MMP activity further supports the tight control of MMPs in complex multifactorial systems while underlining the specificity of each MMP member in vivo. Elastin-derived peptides participate, for example, in the up regulation of MMP-2 and the expression and activation of MT1-MMP [106,107]; activated protein C increases the levels of activated MMP-2, MMP-9 and MMP-13 [108]; and sulfated glycosaminoglycans control the activity of MMP-7 [109] via tethering supplemented by allostery [110]. In contrast, the C-terminal fragment of the procollagen C proteinase enhancer inhibits MMP-2 [111], and membrane-anchored glycoprotein RECK inhibits MMP-2, MMP-9 and MT1-MMP [112]. Two other fragments, the short NC1 domain of collagen XIX and the lumican-derived peptide lumcorin, have been shown to inhibit MT1-MMP activity in vitro and in vivo, with the latter also found to down regulate the expression of MT1-MMP [113,114]. Interestingly, the same structural ECM protein and its different cleavage products may result in opposing effects. For example, HT1080 cancer cells activate pro-MMP-2 in the presence of collagen type IV, a key regulatory mechanism for the acquisition of an invasive potential through the basement membrane [115]. In contrast, the C-terminal region of tumstatin, a proteolytic product of collagen IV by MMP-9, inhibits in vivo the proteolytic cascades of tumor progression, MMPs and plasminogen activation [116], whereas α1 noncollageneous domain of the same collagen prevents activation of proMMP-2 by forming a stable complex in vitro and in vivo [117]. Another example is endostatin, a proteolytic product of collagen XVIII by several MMPs, inhibits the catalytic activity of MMP-2, MT1-MMP, MMP-9 and MMP-13, but appears to have no effect on MMP-8

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Please cite this article as: Gaffney Jean, et al, Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo, Matrix Biol (2015), http://dx.doi.org/10.1016/j.matbio.2015.01.012

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The research leading to this report has received funding from the Israeli Scientific Foundation, Thompson Foundation, EU FP7 and SaveMe project. I.Sa. is the incumbent of the Pontecorvo professorial chair.

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Received 10 December 2014; Received in revised form 18 January 2015; Accepted 18 January 2015 Available online xxxx

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Keywords: Matrix metalloproteinases; Regulation; Extracellular matrix

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† Equal contribution.

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