Function Of Matrix Metalloproteinases Research Articles

High-Throughput Multiplexed Peptide-Centric Profiling Illustrates Both Substrate Cleavage Redundancy and Specificity in the MMP Family

Matrix metalloproteinases (MMPs) play incompletely understood roles in health and disease. Knowing the MMP cleavage preferences is essential for a better understanding of the MMP functions and design of selective inhibitors. To elucidate the cleavage preferences of MMPs, we employed a high-throughput multiplexed peptide-centric profiling technology involving the cleavage of 18,583 peptides by 18 proteinases from the main sub-groups of the MMP family. Our results enabled comparison of the MMP substrates on a global scale, leading to the most efficient and selective substrates. The data validated the accuracy of our cleavage prediction software. This software allows us and others to locate, with nearly 100% accuracy, the MMP cleavage sites in the peptide sequences. In addition to increasing our understanding of both the selectivity and the redundancy of the MMP family, our study generated a roadmap for the subsequent MMP structural-functional studies and efficient substrate and inhibitor design.

Tomato Sl3-MMP, a member of the Matrix metalloproteinase family, is required for disease resistance against Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000.

BackgroundMatrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases. MMPs have been characterized in detail in mammals and shown to play key roles in many physiological and pathological processes. Although MMPs in some plant species have been identified, the function of MMPs in biotic stress responses remains elusive.ResultsA total of five MMP genes were identified in tomato genome. qRT-PCR analysis revealed that expression of Sl-MMP genes was induced with distinct patterns by infection of Botrytis cinerea and Pseudomonas syringae pv. tomato (Pst) DC3000 and by treatment with defense-related hormones such as salicylic acid, jasmonic acid and ethylene precursor 1-amino cyclopropane-1-carboxylic acid. Virus-induced gene silencing (VIGS)-based knockdown of individual Sl-MMPs and disease assays indicated that silencing of Sl3-MMP resulted in reduced resistance to B. cinerea and Pst DC3000, whereas silencing of other four Sl-MMPs did not affect the disease resistance against these two pathogens. The Sl3-MMP-silenced tomato plants responded with increased accumulation of reactive oxygen species and alerted expression of defense genes after infection of B. cinerea. Transient expression of Sl3-MMP in leaves of Nicotiana benthamiana led to an enhanced resistance to B. cinerea and upregulated expression of defense-related genes. Biochemical assays revealed that the recombinant mature Sl3-MMP protein had proteolytic activities in vitro with distinct preferences for specificity of cleavage sites. The Sl3-MMP protein was targeted onto the plasma membrane of plant cells when transiently expressed in onion epidermal cells.ConclusionVIGS-based knockdown of Sl3-MMP expression in tomato and gain-of-function transient expression of Sl3-MMP in N. benthamiana demonstrate that Sl3-MMP functions as a positive regulator of defense response against B. cinerea and Pst DC3000.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-015-0536-z) contains supplementary material, which is available to authorized users.

Nonproteolytic functions of matrix metalloproteinases in pathology and insights for the development of novel therapeutic inhibitors

Structural selectivity - in fact, the lack thereof - has been invoked as an explana- tion for the failure of matrix metalloproteinase (MMP) inhibitors as oncology drugs. However, functional selectivity is needed to develop a good drug. In addition, many drugs (including in oncology) act by interfering with signaling functions. The present market of successful biologicals contains many monoclonal antibodies, such as signaling inhibitors, with antitumor necrosis factor (anti-TNF) being the flagship of an armada. However, aside from its many pathogenic functions, TNF also plays physiological (ie, beneficial) roles. As long as the inhibi - tion of detrimental functions supersedes the negative side effects, anti-TNF will be used. For such reasons, it is critical to know all the functions of MMPs, ideally before inhibitors are used as drugs. Here, we briefly summarize the known catalytic MMP functions and focus on the noncatalytic roles of these proteins, with an emphasis on their signaling effects. Indeed, recent studies have addressed the biology of multimolecular signaling complexes containing MMPs and the tissue inhibitors of metalloproteinases. These complexes are observed in solution (eg, as heteromers or homomultimers) and at the cell surfaces (eg, as docking complexes and signaling receptors). Consequently, a good understanding of the broader contexts - from the molecular, to the cellular and tissue levels - in which such molecular complexes operate will provide essential insights into direct new drug developments. This is exemplified with clinical and recent preclinical successes.

MMPs as Regulators of Tumor Microenvironment

Matrix metalloproteinases (MMPs) are a family of zinc‐dependent endopeptidases with important functions in development, tissue injury and repair and cancer. In cancer MMPs pave the way for tumor cell invasion and metastasis through extracellular matrix degradation as well as with non‐protelytic functions. Due to their ability to cleave, degrade and rearrange ECM molecules, MMPs can modulate a variety of stem cell niches both normal and in neoplastic progression. Indeed, changes in the microenvironment such as overexpression of an MMP can alter the propensity of signaling pathways that promote stem cell expansion and alter neoplastic risk. The abilities of MMPs to influence differentiation processes may be hijacked in cancer. There are also several ways by which MMPs may be influence proliferation during development and also in the tumor microenvironment, since they can alter the bioavailability or functionality of multiple important growth regulating factors. MMPs contribute to tissue invasion based on their ability to cleave ECM and basement membrane components proteolytically, and thereby pave the way through the interstitium for invading tissues or cancer cells. However, not all MMP functions are pro‐cancer. MMP8 may protect from tumor progression. Thus use of inhibitors tthat are specific for particular MMPs, e.g,, antibodies may have promise in the long run therapeutically.Supported by grants from NCI

Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms.

Atherosclerosis is an inflammatory process that involves activation of matrix metalloproteinases (MMPs); MMPs degrade collagen and allow for smooth-muscle cell migration within a vessel. Moreover, this begets an accumulation of other cellular material, resulting in occlusion of the vessel and ischemic events to tissues in need of nutrients. Homocysteine has been shown to activate MMPs via an increase in oxidative stress and acting as a signaling molecule on receptors like the peroxisome proliferator activated receptor-γ and N-methyl-D-aspartate receptor. Nitric oxide has been shown to be beneficial in some cases of deactivating MMPs. However, in other cases, it has been shown to be harmful. Further studies are warranted on the scenarios that are beneficial versus destructive. Hydrogen sulfide (H2S) has been shown to decrease MMP activities in all cases in the literature by acting as an antioxidant and vasodilator. Various MMP-knockout and gene-silencing models have been used to determine the function of the many different MMPs. This has allowed us to discern the role that each MMP has in promoting or alleviating pathological conditions. Furthermore, there has been some study into the MMP polymorphisms that exist in the population. The purpose of this review is to examine the role of MMPs and their polymorphisms on the development of atherosclerosis, with emphasis placed on pathways that involve nitric oxide, hydrogen sulfide, and homocysteine.

Matrix metalloproteinase function in non-mammalian model organisms.

Matrix metalloproteinases (MMPs), adamalysins, astacins, and serralysins are members of the metzincin superfamily of proteases. MMPs constitute a large protein family of both secreted and membrane-tethered enzymes that are synthesized as zymogens (proMMP) and activated by a cysteine-switch mechanism. First described over 50 years ago by Gross and Lapiere as a collagenolytic activity in amphibian tissues, the human MMP family now encompasses 23 different genes whose encoded proteins are capable of cleaving a variety of extracellular matrix protein substrates. Since their expression is upregulated in many cancer cell types, MMPs have received much attention particularly in the areas of tumor progression and metastasis. However, in terms of normal developmental processes, much less is known regarding MMP function and substrate identity. Data from knockout mouse studies support the notion that MMPs are not essential regulators of embryonic development, suggesting redundancy between MMPs or the presence of subtle phenotypes. However, studies on MMP function in other model systems indicate a larger role for MMP-dependent proteolysis during embryonic processes. Here, we review the current knowledge of MMPs from diverse model systems ranging from flowering plants and invertebrates to non-mammalian vertebrates.

Role of Dentin MMPs in Caries Progression and Bond Stability

Dentin can be described as a biological composite with collagen matrix embedded with nanosized hydroxyapatite mineral crystallites. Matrix metalloproteinases (MMPs) and cysteine cathepsins are families of endopeptidases. Enzymes of both families are present in dentin and collectively capable of degrading virtually all extracellular matrix components. This review describes these enzymes and their presence in dentin, mainly focusing on their role in dentin caries pathogenesis and loss of collagen in the adhesive hybrid layer under composite restorations. MMPs and cysteine cathepsins present in saliva, mineralized dentin, and/or dentinal fluid may affect the dentin caries process at the early phases of demineralization. Changes in collagen and noncollagenous protein structure may participate in observed decreases in mechanical properties of caries-affected dentin and reduce the ability of caries-affected dentin to remineralize. These endogenous enzymes also remain entrapped within the hybrid layer during the resin infiltration process, and the acidic bonding agents themselves (irrespective of whether they are etch-and-rinse or self-etch) can activate these endogenous protease proforms. Since resin impregnation is frequently incomplete, denuded collagen matrices associated with free water (which serves as a collagen cleavage reagent for these endogenous hydrolase enzymes) can be enzymatically disrupted, finally contributing to the degradation of the hybrid layer. There are multiple in vitro and in vivo reports showing that the longevity of the adhesive interface is increased when nonspecific enzyme-inhibiting strategies are used. Different chemicals (i.e., chlorhexidine, galardin, and benzalkonium chloride) or collagen cross-linker agents have been successfully employed as therapeutic primers in the bonding procedure. In addition, the incorporation of enzyme inhibitors (i.e., quaternary ammonium methacrylates) into the resin blends has been recently promoted. This review will describe MMP functions in caries and hybrid layer degradation and explore the potential therapeutic role of MMP inhibitors for the development of improved intervention strategies for MMP-related oral diseases.

Implication of matrix metalloproteinases in regulating neuronal disorder.

Neurological disorder is an abnormal condition of the nervous system that occurs due to the structural and biochemical abnormalities of nerves in brain and spinal cord. The nervous system, once exposed, has a limited capacity of self-repair. Neurodegeneration refers to the phenomenon of the structural and functional loss of neurons and the rate of which is accelerated by aging. Recent studies identified the blood brain barrier as hotspot of damage due to neurodegeneration. Depending on the location and severity of damage, the neurons succumb to death through the apoptotic, autophagic and necrotic pathways. The neurological system reorients the structure of neuronal circuits in order to maintain the neuronal plasticity during neurological disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis etc. Matrix metalloproteinases (MMPs), a family of Zn(2+) dependent endopeptidases play an important role in those neurodegenerative disorders. Recent studies implicated the role of MMPs in acute neuroinflammatory damage as well as in chronic neurodegeneration. The critical function of individual MMPs in tissue repair is also very important. MMPs serve important functions in the central nervous system (CNS) during growth and development. Besides, MMPs are important in neuronal damage in acute and chronic conditions as well as repair processes. Studies reveal that MMPs and the tissue inhibitors of metalloproteinases (TIMPs) play pivotal roles in pathogenesis and recovery of neurons. The expression and activities of MMPs are regulated by signaling molecules, TIMPs, cell surface receptors and transcription factors. In this review, we attempt to elucidate the role of MMPs in neurodegeneration and their functional mechanism in repairing the CNS. We also provide information for the therapeutics in neuronal disorder in the perspective of MMP regulation.

A glimpse of matrix metalloproteinases in diabetic nephropathy.

Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Matrix metalloproteinases (MMPs) are extracellular matrix (ECM) degrading enzymes and have complex and specific regulation networks. This includes activation interactions, where one MMP family member activates another. ECM degradation and MMP activation can be initiated by several different stimuli including changes in ECM mechanical properties or intracellular contractility. These mechanical stimuli are known enhancers of metastatic potential. MMP-14 facilitates local ECM degradation and is well known as a major mediator of cell migration, angiogenesis and invasion. Recently, function blocking antibodies have been developed to specifically block MMP-14, providing a useful tool for research as well as therapeutic applications. Here we utilize a selective MMP-14 function blocking antibody to delineate the role of MMP-14 as an activator of other MMPs in response to changes in cellular contractility and ECM stiffness. Inhibition using function blocking antibodies reveals that MMP-14 activates soluble MMPs like MMP-2 and -9 under various mechanical stimuli in the pancreatic cancer cell line, Panc-1. In addition, inhibition of MMP-14 abates Panc-1 cell extension into 3D gels to levels seen with non-specific pan-MMP inhibitors at higher concentrations. This strengthens the case for MMP function blocking antibodies as more potent and specific MMP inhibition therapeutics.

MMPs in the Neuroretina and Optic Nerve: Modulators of Glaucoma Pathogenesis and Repair?

Multiple studies in glaucoma patients and in animal models of spontaneous and experimentally-induced glaucoma, reported changes in the expression and activity of several matrix metalloproteinases (MMPs) in the retina, optic nerve, aqueous humor, and trabecular meshwork. These data have led to the hypothesis that MMPs might be involved in glaucoma onset and/or disease progression. However, reports are conflicting and research aiming at providing a clear definition of their causative role is lacking. In glaucoma, MMPs are thought to act at two different levels. In the trabecular meshwork, they fine-tune the aqueous humor outflow rate and intraocular pressure, in the neuroretina and optic nerve, however, their role during glaucoma disease progression is much less clear. This review provides a comprehensive overview of the research conducted on the expression and function of MMPs in the retina and optic nerve, and on the elucidation of their potential involvement during glaucoma pathogenesis. Additionally, we describe the insecure balance between detrimental and potential beneficial MMP activities during central nervous system recovery and how MMP-based therapies could help to overcome the current pitfalls in the development of retinal ganglion cell neuroprotection and axon regeneration approaches for the treatment of glaucoma.

Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice

Proline-rich protein tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family. We used Pyk2 knockout (Pyk2-KO) mice to study the role of Pyk2 in cutaneous wound repair. We report that the rate of wound closure was delayed in Pyk2-KO compared with control mice. To examine whether impaired wound healing of Pyk2-KO mice was caused by a keratinocyte cell-autonomous defect, the capacities of primary keratinocytes from Pyk2-KO and wild-type (WT) littermates to heal scratch wounds in vitro were compared. The rate of scratch wound repair was decreased in Pyk2-KO keratinocytes compared with WT cells. Moreover, cultured human epidermal keratinocytes overexpressing the dominant-negative mutant of Pyk2 failed to heal scratch wounds. Conversely, stimulation of Pyk2-dependent signaling via WT Pyk2 overexpression induced accelerated scratch wound closure and was associated with increased expression of matrix metalloproteinase (MMP)-1, MMP-9, and MMP-10. The Pyk2-stimulated increase in the rate of scratch wound repair was abolished by coexpression of the dominant-negative mutant of PKCδ and by GM-6001, a broad-spectrum inhibitor of MMP activity. These results suggest that Pyk2 is essential for skin wound reepithelialization in vivo and in vitro and that it regulates epidermal keratinocyte migration via a pathway that requires PKCδ and MMP functions.

Translating Koch’s Postulates to Identify Matrix Metalloproteinase Roles in Postmyocardial Infarction Remodeling

The first matrix metalloproteinase (MMP) was described in 1962; and since the 1990s, cardiovascular research has focused on understanding how MMPs regulate many aspects of cardiovascular pathology from atherosclerosis formation to myocardial infarction and stroke. Although much information has been gleaned by these past reports, to a large degree MMP cardiovascular biology remains observational, with few studies homing in on cause and effect relationships. Koch's postulates were first developed in the 19th century as a way to establish microorganism function and were modified in the 20th century to include methods to establish molecular causality. In this review, we outline the concept for establishing a similar approach to determine causality in terms of MMP functions. We use left ventricular remodeling postmyocardial infarction as an example, but this approach will have broad applicability across both the cardiovascular and the MMP fields.

Diverse functions of matrix metalloproteinases during fibrosis

ABSTRACTFibrosis – a debilitating condition that can occur in most organs – is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis – that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process – experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.

Chapter One - Matrix Metalloproteinases in Coronary Artery Disease

Matrix metalloproteinases (MMP) are a family of zinc-containing endoproteinases that degrade extracellular matrix (ECM) components. MMP have important roles in the development, physiology and pathology of cardiovascular system. Metalloproteases also play key roles in adverse cardiovascular remodeling, atherosclerotic plaque formation and plaque instability, vascular smooth muscle cell (SMC) migration and restenosis that lead to coronary artery disease (CAD), and progressive heart failure. The study of MMP in developing animal model cardiovascular systems has been helpful in deciphering numerous pathologic conditions in humans. Increased peripheral blood MMP-2 and MMP-9 in acute coronary syndrome (ACS) may be useful as noninvasive tests for detection of plaque vulnerability. MMP function can be modulated by certain pharmacological drugs that can be exploited for treatment of ACS. CAD is a polygenic disease and hundreds of genes contribute toward its predisposition. A large number of sequence variations in MMP genes have been identified. Case-control association studies have highlighted their potential association with CAD and its clinical manifestations. Although results thus far are inconsistent, meta-analysis has demonstrated that MMP-3 Glu45Lys and MMP-9 1562C/T gene polymorphisms were associated with CAD risk.

Tetracycline Derivative Minocycline Inhibits Autophagy and Inflammation in Concanavalin-A-Activated Human Hepatoma Cells

Inhibition of soluble matrix metalloproteinase (MMP) activity is among the non-antibiotic cellular effects exerted by the anti-inflammatory tetracycline derivative minocycline. The impact of minocycline on the signal transduction functions of membrane-bound MMPs is however unknown. We assessed minocycline in a concanavalin-A (ConA)-activated human HepG2 hepatoma cell model, a condition known to increase the expression of membrane type-1 MMP (MT-MMP) and to trigger inflammatory and autophagy processes. We found that minocycline inhibited ConA-induced formation of autophagic acidic vacuoles, green fluorescent microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta formation, gene and protein expression of autophagy biomarker BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), invasion biomarker MT1-MMP, and inflammation biomarker cyclooxygenase (COX)-2. Gene silencing of MT1-MMP abrogated ConA-induced formation of autophagic acidic vacuoles and ConA-induced expressions of BNIP3 and COX-2. Minocycline was also shown to inhibit ConA-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation as well as gene expression of NANOS1, a biomarker believed to colocalize with MT1-MMP and the specific silencing of which further inhibited ConA-induced STAT3 phosphorylation. Collectively, our data demonstrate that part of minocycline’s effects on autophagy could be exerted through the inhibition of MT1-MMP signaling functions, which contribute to the autophagy and inflammatory phenotype of ConA-activated HepG2 cells.

Role of matrix metalloproteinases (MMPS) in periodontitis and its management

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix (ECM) macromolecules. The activity of MMPs is seen not only during normal organogenesis and wound healing, but also in pathological condition like inflammatory diseases. MMP synthesis and functions are regulated by transcriptional activation, post-transcriptional processing and by a family of endogenous inhibitors collectively known as tissue inhibitors of metalloproteinases (TIMPs). The balance of MMPs to TIMPs therefore determines matrix turnover, where either an excess of MMPs or a deficit of TIMPs may result in excess ECM degradation. This review describes the role of MMPs in periodontitis and its management.

Protective effect of exogenous matrix metalloproteinase-9 on chronic renal failure

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have pivotal functions in extracellular matrix turnover and are involved in chronic kidney diseases. However, the exact functions of MMPs in chronic renal failure (CRF) have yet to be demonstrated. The aim of the present study was to examine the effects of MMP-9 on CRF. An adenine-induced model of CRF was generated in rabbits. Following the injection of MMP-9 into the renal arteries of the rabbits, significant improvements in renal morphology and serum levels of creatinine and urea nitrogen were observed. Furthermore, MMP-9 administration was shown to decrease the serum TIMP-1 concentration and upregulate renal MMP-9 expression. These results demonstrate a directly protective role for MMP-9 in CRF.

Pacing-induced cardiomyopathy: pathophysiological insights through matrix metalloproteinases

Pacing-induced ventricular dysfunction and pacing-induced cardiomyopathy (PiCMP) are recognized complications of chronic right ventricular pacing. Alterations in myocardial perfusion and sympathetic innervation contribute to the development of pacing-induced heart disease. However, it is unlikely that these are the only processes involved. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the collagenous extracellular matrix and play a central role in left ventricular remodelling during the development of heart failure. While the pathophysiological mechanisms and altered MMP expression that occur in chronic pressure overload, ischaemic and non-ischaemic dilated cardiomyopathy have been defined, those that occur in the clinicalsetting of pacing-induced ventricular dysfunction and PiCMP have not been reported. Here we review the clinical epidemiology of pacing-induced ventricular dysfunction and discuss how data derived from animal models provide insight into how changes in MMP expression and function contribute to the development of PiCMP. The review concludes by exploring pacing strategies that may be used to prevent pacing-induced ventricular dysfunction.

TNFα cleavage beyond TACE/ADAM17: matrix metalloproteinase 13 is a potential therapeutic target in sepsis and colitis

For decades, matrix metalloproteinases (MMPs) have been described as rather unspecific matrix‐ and collagen‐degrading enzymes. Accordingly, this group of proteases was mainly associated with tissue remodeling and pathologic conditions such as tumour development and metastasis. However, broad spectrum MMP inhibitors completely failed in cancer therapy. Recent studies with gene deficient mice revealed more specific functions of MMPs, e.g . the cleavage of chemokines, thereby stimulating inflammatory responses (Dufour & Overall, 2013). Additionally, mass spectrometry‐based proteomic techniques allowed for the identification of hundreds of new substrates of MMPs, giving rise to unexpected biological activity of these proteases in health and disease. MMP13 is known to be one of few collagenases capable of cleaving rigid collagen fibrils. This ability is based on a complex unfolding mechanism of the triple‐helical collagen structure. Therefore, MMP13 biology is well studied in bone and cartilage turnover but little is known about other functions. In this issue, Libert and coworkers report on a pro‐inflammatory activity of MMP13 not by ‘simply’ degrading extracellular matrix but through the release of biologically active soluble TNFα from its membrane bound precursor form. Ectodomain shedding of TNFα is a paracrine signaling event in inflammation performed by the metalloprotease tumour necrosis factor α converting enzyme (TACE, also known as ADAM17) (Scheller et al, 2011). Although TACE/ADAM17 is believed to be the major sheddase of TNFα, Vandenbroucke et al demonstrated that after LPS‐induced sepsis and DSS‐induced colitis, MMP13 is up‐regulated and cleaves TNFα. This leads to ER‐stress and mucus depletion resulting in an increased interaction of bacteria with the intestinal epithelium. Moreover, elevated levels of bioactive TNFα affect the intestinal permeability through endocytosis of tight junction proteins, thereby increasing systemic inflammation. All these events were abolished in MMP13 deficient mice, resulting in increased survival of MMP13 knockout animals, when treated with LPS or DSS. …