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The FEBS Journal Dec 2021Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that were first discovered as proteases, which target and cleave extracellular proteins. During the... (Review)
Review
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that were first discovered as proteases, which target and cleave extracellular proteins. During the past 20 years, however, intracellular roles of MMPs were uncovered and research on this new aspect of their biology expanded. MMP-2 is the first of this protease family to be reported to play a crucial intracellular role where it cleaves several sarcomeric proteins inside cardiac myocytes during oxidative stress-induced injury. Beyond MMP-2, currently at least eleven other MMPs are known to function intracellularly including MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-23 and MMP-26. These intracellular MMPs are localized to different compartments inside the cell including the cytosol, sarcomere, mitochondria, and the nucleus. Intracellular MMPs contribute to the pathogenesis of various diseases. Cardiovascular renal disorders, inflammation, and malignancy are some examples. They also exert antiviral and bactericidal effects. Interestingly, MMPs can act intracellularly through both protease-dependent and protease-independent mechanisms. In this review, we will highlight the intracellular mechanisms of MMPs activation, their numerous subcellular locales, substrates, and roles in different pathological conditions. We will also discuss the future direction of MMP research and the necessity to exploit the knowledge of their intracellular targets and actions for the design of targeted inhibitors.
Topics: Animals; Cardiovascular Diseases; Humans; Matrix Metalloproteinases; Neoplasms
PubMed: 33405316
DOI: 10.1111/febs.15701 -
Pharmacological Reviews Jul 2022The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix... (Review)
Review
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
Topics: Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Proteolysis
PubMed: 35738680
DOI: 10.1124/pharmrev.121.000349 -
International Journal of Molecular... Dec 2020Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.
Topics: Chronic Disease; Diabetes Mellitus; Extracellular Matrix; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Neovascularization, Physiologic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases
PubMed: 33419373
DOI: 10.3390/ijms21249739 -
Life Sciences Oct 2019Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA... (Review)
Review
Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA results in the loss of joint function, usually accompanied by severe pain, and are the most common type of arthritis, affecting more than 10% of adults. The characteristic signs of OA are progressive cartilage destruction and, eventually, complete loss of chondrocytes. A key enzyme responsible for these degenerative changes in cartilage is matrix metalloproteinase-13 (MMP-13), which is thought to be a major contributor to the degenerative process occurring during OA pathogenesis. The aim of the present review is to shed light on the general role of MMPs, with special emphasis on MMP-13, in the induction of OA and the general basis of OA treatment. The pathogenic mechanism of this highly prevalent disease is not clear, and no effective disease-modifying treatment is currently available. Any updated information about OA treatment in human patients will also benefit companion animals such as horses and dogs, which also suffer from OA. Selective inhibition of MMP-13 seems to be an attractive therapeutic strategy.
Topics: Animals; Cartilage, Articular; Drug Discovery; Extracellular Matrix; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Osteoarthritis
PubMed: 31445934
DOI: 10.1016/j.lfs.2019.116786 -
International Journal of Molecular... Feb 2022Severe periodontitis, a destructive inflammatory disease of the supporting tissues of the teeth, ranks sixth in terms of global spread, affecting about 11% of the... (Review)
Review
Severe periodontitis, a destructive inflammatory disease of the supporting tissues of the teeth, ranks sixth in terms of global spread, affecting about 11% of the population. Metalloproteinases (MMPs) are extracellular matrix (ECM) macromolecules that are important in cellular development and morphogenesis, and they are capable of activating growth factors in their proximity, cell surface receptors, and adhesion molecules. MMPs are part of a major family of zinc-dependent endopeptidases, and their activity is modulated and regulated by certain inhibitors known as tissue metalloproteinase inhibitors (TIMPs). Because type I collagen is the major component of the periodontal extracellular matrix, special attention has been paid to the role of collagenases, especially MMP-8 and MMP-13 and gelatinases, MMP-2 and MMP-9, in periodontal diseases. In fact, MMP-8 (or collagenase 2) is currently one of the most promising biomarkers for periodontitis in oral fluids. Among them, salivary MMP-9 has been shown to be a more sensitive marker for periodontal inflammation during orthodontic treatment, which opens new perspectives in reducing periodontal hazards during such treatments. Both MMP-8 and MMP-9 are extremely valuable diagnostic tools in treating periodontitis, and future studies and healthcare policies should focus on implementing more accessible methods of chairside testing in order to reduce the prevalence of this disease.
Topics: Gingival Crevicular Fluid; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Periodontitis
PubMed: 35163727
DOI: 10.3390/ijms23031806 -
Current Medicinal Chemistry 2023Matrix metalloproteinases (MMPs) are a family of zinc-containing proteases that participate in many physiological and pathological processes in vivo. Recently, the MMP... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-containing proteases that participate in many physiological and pathological processes in vivo. Recently, the MMP network has been established according to a deeper understanding of its functions. Some MMPs have been also regarded as biomarkers of various diseases, including inflammation, nerve diseases, and cancers. MMP labelling has been thus paid more attention in recent decades. Accordingly, both reagents and technologies for MMP labelling have been rapidly developed. Here we summarize the recent development of some MMP labelling methods. This review was identified through keyword (MMPs; labelling; etc.) searches in the ScienceDirect database, Scifinder, Web of Science, and PubMed for which typical cases were used for an inductive overview. In spite of the advances in MMP labelling, selective labelling of a specific MMP is still an open issue. We hope that this article can be helpful in developing specific MMP labelling methods in future.
Topics: Humans; Matrix Metalloproteinases; Neoplasms; Inflammation
PubMed: 36642878
DOI: 10.2174/0929867330666230113121728 -
American Journal of Physiology. Cell... Oct 2022Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including... (Review)
Review
Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including metalloproteinases. The expression and activity of all metalloproteinases are under strict control, and their deregulation is often associated with diseases or chronic conditions, thereby being considered popular targets for developing new therapeutics. This review will highlight metalloproteinases of the MMP and ADAM families with functions in dermal homeostasis and give some insights into the mechanisms regulating their activity and expression. Furthermore, we discuss how the dysregulation of the most prominent family members affects dermal homeostasis by triggering disease development and influencing progression, focusing on cancer and aging. Here, recent discoveries and new approaches that target or exploit metalloproteinase activity in therapy are emphasized. The potential of naturally derived components in regulating metalloproteinase expression and activity in disease is discussed.
Topics: Extracellular Matrix; Homeostasis; Humans; Matrix Metalloproteinases; Neoplasms; Proteolysis
PubMed: 36094433
DOI: 10.1152/ajpcell.00450.2021 -
International Journal of Molecular... Mar 2021Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the... (Review)
Review
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor-microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.
Topics: Animals; Female; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinases; Ovarian Neoplasms; Proteolysis; Tumor Microenvironment
PubMed: 33810259
DOI: 10.3390/ijms22073403 -
JCI Insight May 2022It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to...
It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to upregulate MMPs 1, 3, and 9, which then degrade collagen and other extracellular matrix components to produce wrinkles. However, these MMPs are expressed at relatively low levels and correlate poorly with wrinkles, suggesting that another mechanism distinct from ROS and MMP1/3/9 may be more directly associated with photoaging. Here we show that MMP2, which degrades type IV collagen, is abundantly expressed in human skin, increases with age in sun-exposed skin, and correlates robustly with aryl hydrocarbon receptor (AhR), a transcription factor directly activated by UV-generated photometabolites. Through mechanistic studies with HaCaT human immortalized keratinocytes, we found that AhR, specificity protein 1 (SP1), and other pathways associated with DNA damage are required for the induction of both MMP2 and MMP11 (another MMP implicated in photoaging), but not MMP1/3. Last, we found that topical treatment with AhR antagonists vitamin B12 and folic acid ameliorated UVB-induced wrinkle formation in mice while dampening MMP2 expression in the skin. These results directly implicate DNA damage in photoaging and reveal AhR as a potential target for preventing wrinkles.
Topics: Animals; DNA Damage; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Mice; Reactive Oxygen Species; Receptors, Aryl Hydrocarbon; Skin Aging
PubMed: 35316219
DOI: 10.1172/jci.insight.156344 -
Bioconjugate Chemistry Aug 2023Matrix metalloproteinases (MMPs) are a class of endopeptidases that are dependent on zinc and facilitate the degradation of extracellular matrix (ECM) proteins, thereby... (Review)
Review
Matrix metalloproteinases (MMPs) are a class of endopeptidases that are dependent on zinc and facilitate the degradation of extracellular matrix (ECM) proteins, thereby playing pivotal parts in human physiology and pathology. MMPs regulate normal tissue and cellular functions, including tissue development, remodeling, angiogenesis, bone formation, and wound healing. Several diseases, including cancer, inflammation, cardiovascular diseases, and nervous system disorders, have been linked to dysregulated expression of specific MMP subtypes, which can promote tumor progression, metastasis, and inflammation. Various MMP-responsive drug delivery and release systems have been developed by harnessing cleavage activities and overexpression of MMPs in affected regions. Herein, we review the structure, substrates, and physiological and pathological functions of various MMPs and highlight the strategies for designing MMP-responsive nanoparticles to improve the targeting efficiency, penetration, and protection of therapeutic payloads.
Topics: Humans; Matrix Metalloproteinases; Neoplasms; Drug Delivery Systems; Extracellular Matrix; Matrix Metalloproteinase Inhibitors
PubMed: 37533285
DOI: 10.1021/acs.bioconjchem.3c00266