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Journal of Ocular Pharmacology and... May 2020Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from and studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.
Topics: Administration, Topical; Animals; Antihypertensive Agents; Bimatoprost; Ciliary Body; Collagen; Drug Implants; Extracellular Matrix; Glaucoma; Homeostasis; Humans; Intraocular Pressure; Matrix Metalloproteinases; Models, Animal; Prostaglandins, Synthetic; Tissue Inhibitor of Metalloproteinases; Trabecular Meshwork
PubMed: 32233938
DOI: 10.1089/jop.2019.0146 -
International Journal of Molecular... Apr 2020Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a...
Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a disintegrin and metalloproteinase domain) and 19 secreted ADAMTSs (a disintegrin and metalloproteinase thrombospondin domain). The many setbacks from the clinical trials of broad-spectrum MMP inhibitors for cancer indications in the late 1990s emphasized the extreme complexity of the participation of these proteolytic enzymes in biology. This editorial mini-review summarizes the Special Issue, which includes four review articles and 10 original articles that highlight the versatile roles of MMPs, ADAMs, and ADAMTSs, in normal physiology as well as in neoplastic and destructive processes in tissue. In addition, we briefly discuss the unambiguous involvement of MMPs in wound healing.
Topics: ADAM Proteins; Animals; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Protein Domains; Thrombospondins
PubMed: 32290531
DOI: 10.3390/ijms21082678 -
Experimental Dermatology Jan 2021The incidence of cutaneous keratinocyte-derived cancers is increasing globally. Basal cell carcinoma (BCC) is the most common malignancy worldwide, and cutaneous... (Review)
Review
The incidence of cutaneous keratinocyte-derived cancers is increasing globally. Basal cell carcinoma (BCC) is the most common malignancy worldwide, and cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. BCC can be classified into subtypes based on the histology, and these subtypes are classified further into low- and high-risk tumors. There is an increasing need to identify new therapeutic strategies for the treatment of unresectable and metastatic cSCC, and for aggressive BCC variants such as infiltrating, basosquamous or morpheaform BCCs. The most important risk factor for BCC and cSCC is solar UV radiation, which causes genetic and epigenetic alterations in keratinocytes. Similar gene mutations are noted already in sun-exposed normal skin emphasizing the role of the alterations in the tumor microenvironment in the progression of cSCC. Early events in cSCC progression are alterations in the composition of basement membrane and dermal extracellular matrix induced by influx of microbes, inflammatory cells and activated stromal fibroblasts. Activated fibroblasts promote inflammation and produce growth factors and proteolytic enzymes, including matrix metalloproteinases (MMPs). Transforming growth factor-β produced by tumor cells and fibroblasts induces the expression of MMPs by cSCC cells and promotes their invasion. Fibroblast-derived keratinocyte growth factor suppresses the malignant phenotype of cSCC cells by inhibiting the expression of several MMPs. These findings emphasize the importance of interplay of tumor and stromal cells in the progression of cSCC and BCC and suggest tumor microenvironment as a therapeutic target in cSCC and aggressive subtypes of BCC.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Fibroblast Growth Factor 7; Fibroblasts; Humans; Keratinocytes; Matrix Metalloproteinases; Skin Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32869366
DOI: 10.1111/exd.14183 -
Naunyn-Schmiedeberg's Archives of... Jan 2022Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological... (Review)
Review
Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological processes. We aim to review the MMP inhibition from a clinical perspective and its possible therapeutic use in the future. MMPs play a role in various neurodegenerative and cerebrovascular diseases such as large artery atherosclerosis and ischemic stroke; for example, MMPs increase blood-brain barrier permeability favoring neuroinflammation. Synthetic MMPs inhibitors have been tested mostly in oncological trials and failed to demonstrate efficacy; some of them were discontinued because of the severe adverse reactions. Tetracyclines, in submicrobial doses, act as an MMP inhibitor, although tetracyclines have not yet been proven effective in several neurological conditions in which they were tested against placebo; it is uncertain whether there may be a use for tetracyclines in cerebrovascular disease, as a neuroprotective agent or in dolichoectasia.
Topics: Animals; Blood-Brain Barrier; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Nervous System Diseases; Neuroinflammatory Diseases; Neuroprotective Agents; Tetracyclines
PubMed: 34851449
DOI: 10.1007/s00210-021-02188-x -
Biomolecules May 2020Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix... (Review)
Review
Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.
Topics: Animals; Drug Discovery; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases
PubMed: 32380782
DOI: 10.3390/biom10050717 -
International Journal of Molecular... Jul 2023Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of... (Review)
Review
Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.
Topics: Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasms; Matrix Metalloproteinases; Proteolysis; Extracellular Matrix
PubMed: 37569509
DOI: 10.3390/ijms241512133 -
Clinical Oral Investigations Jul 2019Matrix metalloproteinase (MMP) expression has been associated with tissue development, invasive cancer cell behavior, and inflammation. The associations of increased... (Review)
Review
OBJECTIVES
Matrix metalloproteinase (MMP) expression has been associated with tissue development, invasive cancer cell behavior, and inflammation. The associations of increased expression of MMPs with diseases have led to intensive research activities to develop MMP inhibitors. Here, the questions are addressed which associations between increased levels of any MMP with dental diseases may be cause or consequence, whether MMP levels may be of diagnostic value and whether and which MMP inhibitors need further investigations for use in dental diseases.
METHODS
To study the role of MMPs and to discriminate between cause or consequence, the literature about measurements of MMPs and about the use of inhibitory drugs and genetic knockout animal models in dentistry was compared.
RESULTS
The only FDA-approved treatment with MMP inhibitors is tetracyclines for periodontitis, whereas a diagnostic test for activated MMP-8 in oral fluids is valued in practical periodontology. The MMP literature in dentistry is artificially skewed to the gelatinases MMP-2 and MMP-9 and to enamelysin, alias MMP-20. The basis for this observation is, respectively, the widely used and sensitive technique of gelatin zymography and enamel proteins as substrates of MMP-20. Studies on additional MMPs are gaining interest in dentistry and MMP inhibitors may provide new applications. In addition, drugs with proven effects for the treatment of dental diseases may be found to act through MMP inhibition.
CONCLUSION AND RELEVANCE
In conclusion, research on MMPs and inhibitors may provide practical applications beyond diagnosis and treatment of periodontitis and will be, directly or indirectly, beneficial for patients with dental or periodontal diseases.
Topics: Animals; Dentistry; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Periodontitis
PubMed: 31093743
DOI: 10.1007/s00784-019-02915-y -
Calcified Tissue International Sep 2021Metalloproteinases were first identified as collagen cleaving enzymes and are now appreciated to play important roles in a wide variety of biological processes. The... (Review)
Review
Metalloproteinases were first identified as collagen cleaving enzymes and are now appreciated to play important roles in a wide variety of biological processes. The aberrant activity and dysregulation of the metalloproteinase family are linked to numerous diseases including cardiovascular and pulmonary diseases, chronic wounds, cancer, fibrosis and arthritis. Osteoarthritis (OA) is the most prevalent age-related joint disorder that causes pain and disability, but there are no disease-modifying drugs available. The hallmark of OA is loss of articular cartilage and elevated activities of matrix-degrading metalloproteinases are responsible. These enzymes do not exist in isolation and their activity is tightly regulated by a number of processes, such as transcription, proteolytic activation, interaction with their inhibitors, cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu. Here, we describe the functions and roles of metalloproteinase family in OA pathogenesis. We highlight recent studies that have illustrated novel mechanisms regulating their extracellular activity and impairment of such regulations that lead to the development of OA. We also discuss how to stop or slow down the degenerative processes by targeting aberrant metalloproteinase activity, which may in future become therapeutic interventions for the disease.
Topics: Cartilage, Articular; Collagen; Extracellular Matrix; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinases; Osteoarthritis
PubMed: 32772139
DOI: 10.1007/s00223-020-00739-7 -
Anatomical Record (Hoboken, N.J. : 2007) Jun 2020It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many... (Review)
Review
It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many of the hallmarks associated with them. The activity of these enzymes has been directly implicated in extracellular matrix remodeling, the processing of growth factors and receptors, the modulation of cell migration, proliferation, and invasion, the epithelial to mesenchymal transition, the regulation of immune responses, and the control of angiogenesis. Certain MMP family members have been validated as biomarkers of a variety of human cancers including those of the breast, brain, pancreas, prostate, ovary, and others. The related metalloproteinases, the A disintegrin and metalloproteinases (ADAMs), share a number of these functions as well. Here, we explore these essential metalloproteinases and some of their disease-associated activities in detail as well as some of their complementary translational potential. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.
Topics: Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Matrix Metalloproteinases; Neoplasms; Neovascularization, Pathologic
PubMed: 31168956
DOI: 10.1002/ar.24188 -
Frontiers in Immunology 2022Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral... (Review)
Review
Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.
Topics: Basigin; Brain Ischemia; Cerebral Hemorrhage; Humans; Matrix Metalloproteinases; Stroke
PubMed: 36119117
DOI: 10.3389/fimmu.2022.986469