• Blood-brain barrier
• Extracellular matrix metalloproteinase inducer
• Intracerebral hemorrhage
• Matrix metalloproteinases
• Neuroinflammation

• Humans
• Basigin/metabolism
• Matrix Metalloproteinases/metabolism
• Cerebral Hemorrhage/metabolism
• Cerebral Hemorrhage/drug therapy
• Animals
• Blood-Brain Barrier/metabolism

• Cow
• Endometrium
• Gelatinase
• Luteal phase
• Postpartum period

• Animals
• Female
• Cattle
• Endometrium/metabolism
• Postpartum Period
• Parturition/physiology
• Metalloproteases/metabolism
• Pregnancy
• Fertilization/physiology
• Tissue Inhibitor of Metalloproteinases/metabolism
• Tissue Inhibitor of Metalloproteinases/genetics
• Tissue Inhibitor of Metalloproteinase-1/metabolism
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Tissue Inhibitor of Metalloproteinase-2/metabolism
• Tissue Inhibitor of Metalloproteinase-2/genetics

• PICT 2017-2197 Argentine National Agency for the Promotion of Science and Technology

• Kidney injury
• MMP9
• MMP9 inhibitors
• MMPs
• Nephropathy
• Renal fibrosis

• Animals
• Humans
• Extracellular Matrix/metabolism
• Fibrosis
• Kidney/pathology
• Kidney/metabolism
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinase Inhibitors/pharmacology
• Matrix Metalloproteinase Inhibitors/therapeutic use

• Animals
• Matrix Metalloproteinase 14/metabolism
• Matrix Metalloproteinase 14/genetics
• Fibroblasts/metabolism
• Cell Survival
• Apoptosis
• Mice
• Mice, Knockout
• Collagen Type I/metabolism
• Collagen Type I/genetics
• Integrin beta1/metabolism
• Integrin beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Dermis/metabolism
• Dermis/cytology
• Cells, Cultured
• Extracellular Matrix/metabolism
• Mice, Inbred C57BL
• Skin/metabolism

• P41 EB015890 NIBIB NIH HHS
• Margolies Family Discovery Fund for Cancer Research
• T32 CA009676 NCI NIH HHS
• Breast Cancer Research Foundation
• R01 CA071699 NCI NIH HHS
• R01 HL085339 NHLBI NIH HHS
• R01-CA-071699-16-A1 NIH HHS
• National Institutes of Health

• MT1-MMP
• extracellular matrix
• integrins
• invadosomes
• matrix-metalloproteinases
• metastatic cascade
• therapeutic targets
• tumor microenvironment

Previous study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed.

In this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes.

We found that, MMP1, MMP3, MMP7, MMP9–MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time.

This study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.

• MMPs
• colorectal cancer
• expression
• prognosis
• tumor stage

• Invadopodia
• Metastasis
• Pancreatic cancer
• Therapeutic targets

• Akt
• Glioblastoma
• Invasion
• Migration
• PI3K
• Protease
• Rho GTPase

• Invadopodia
• Monocytes
• Pancreatic ductal adenocarcinoma
• TIMP2
• Tumor microenvironment

• Cystic fibrosis
• inflammation
• therapeutic targets

Dysregulation in the extracellular matrix (ECM) microenvironment surrounding the retinal pigment epithelium (RPE) has been implicated in the etiology of proliferative vitreoretinopathy and age-related macular degeneration. The regulation of ECM remodeling by RPE cells is not well understood. We show that membrane-type matrix metalloproteinase 14 (MMP14) is central to ECM degradation at the focal adhesions in human ARPE19 cells. The matrix degradative activity, but not the assembly, of the focal adhesion is regulated by chloride intracellular channel 4 (CLIC4). CLIC4 is co-localized with MMP14 in the late endosome. CLIC4 regulates the proper sorting of MMP14 into the lumen of the late endosome and its proteolytic activation in lipid rafts. CLIC4 has the newly-identified “late domain” motif that binds to MMP14 and to Tsg101, a component of the endosomal sorting complex required for transport (ESCRT) complex. Unlike the late domain mutant CLIC4, wild-type CLIC4 can rescue the late endosomal sorting defect of MMP14. Finally, CLIC4 knockdown inhibits the apical secretion of MMP2 in polarized human RPE monolayers. These results, taken together, demonstrate that CLIC4 is a novel matrix microenvironment modulator and a novel regulator for late endosomal cargo sorting. Moreover, the late endosomal sorting of MMP14 actively regulates its surface activation in RPE cells.

• Gelatinase
• MMP2
• Microglia
• Müller glia
• Regeneration
• TIMP2
• TIMP3

Due to their capacity to process different proteins of the extracellular matrix (ECM), matrix metalloproteinases (MMPs) were initially described as a family of secreted proteases, functioning as main ECM regulators. However, through proteolytic processing of various biomolecules, MMPs also modulate intra- and extracellular pathways and networks. Thereby, they are functionally implicated in the regulation of multiple physiological and pathological processes. Consequently, MMP activity is tightly regulated through a combination of epigenetic, transcriptional, and post-transcriptional control of gene expression, proteolytic activation, post-translational modifications (PTMs), and extracellular inhibition. In addition, MMPs, their substrates and ECM binding partners are frequently modified by PTMs, which suggests an important role of PTMs in modulating the pleiotropic activities of these proteases. This review summarizes the recent progress towards understanding the role of PTMs (glycosylation, phosphorylation, glycosaminoglycans) on the activity of several members of the MMP family.

• MMPs
• PTMs
• glycosaminoglycans
• glycosylation
• phosphorylation

• cell surface proteolysis
• cell-based assay
• collagenolysis
• matrix metalloproteinase
• protease inhibitor

• Basement Membrane/chemistry
• Biocompatible Materials
• Collagen/chemistry
• Drug Combinations
• Growth Substances
• Humans
• Laminin/chemistry
• Matrix Metalloproteinases/analysis
• Plasminogen Activator Inhibitor 1/analysis
• Proteoglycans/chemistry
• Tissue Inhibitor of Metalloproteinase-1/analysis
• Tissue Inhibitor of Metalloproteinase-2/analysis
• Tissue Inhibitor of Metalloproteinases/analysis
• Urokinase-Type Plasminogen Activator/analysis

• 1 P20 RR15566 NCRR NIH HHS
• 1 R15 CA-82139 NCI NIH HHS

• APSs
• NGS
• Obesity
• RNA biogenesis

• antiresorptive
• osteoblasts
• osteoclasts
• osteoporosis

• Aneurysm
• Angiogenesis
• Atherosclerosis
• Cell signaling
• Extracellular matrix
• Hypertension
• Smooth muscle
• TIMPs

• Animals
• Humans
• Matrix Metalloproteinase Inhibitors/pharmacology
• Matrix Metalloproteinases/chemistry
• Matrix Metalloproteinases/metabolism
• Substrate Specificity/drug effects
• Tissue Distribution/drug effects
• Vascular Diseases/enzymology
• Vascular Diseases/physiopathology
• Vascular Remodeling/drug effects

• R01 HL065998 NHLBI NIH HHS
• R21 HL111775 NHLBI NIH HHS

• ERO1α
• MT1-MMP
• autophagy
• collagen
• endoplasmic reticulum (ER)
• hepatic stellate cell (HSC)
• protein disulfide isomerase

• Hypertension
• Placenta
• Preeclampsia
• Remodeling
• Uterine artery
• Uterus

• Cell signaling
• Collagen
• Extracellular matrix
• Protein degradation
• Proteinases
• Remodeling

• PI3-kinase/AKT pathway
• TIMPs
• c-Src
• lung adenocarcinoma
• tumorigenesis

• adipose-derived stem cells
• angiogenesis
• matrix metalloproteinase
• extracellular matrix remodeling
• endothelial cells

• Adipocytes/cytology
• Adipose Tissue/cytology
• Coculture Techniques
• Collagen/metabolism
• Endothelium, Vascular/metabolism
• Extracellular Matrix/metabolism
• Human Umbilical Vein Endothelial Cells
• Humans
• Matrix Metalloproteinases/metabolism
• Neoplasm Invasiveness
• Neovascularization, Pathologic
• Stem Cells/cytology
• Tissue Engineering/methods
• Vascular Endothelial Growth Factor A/metabolism

• S10RR025502 NCRR NIH HHS
• U54CA143876 NCI NIH HHS
• R01 CA185293 NCI NIH HHS
• U54 CA143876 NCI NIH HHS
• UL1 TR002384 NCATS NIH HHS
• S10 RR025502 NCRR NIH HHS
• R01CA185293 NCI NIH HHS
• S10OD010605 NIH HHS
• S10 OD010605 NIH HHS

• mmps
• timps
• mirna
• epigenetics
• extracellular matrix
• atherosclerosis
• cardiovascular
• review

• Humans
• Matrix Metalloproteinases/metabolism
• Vascular Diseases/enzymology

• R01 HL104103 NHLBI NIH HHS
• R01 HL108621 NHLBI NIH HHS
• R01 NS084823 NINDS NIH HHS
• HL-108621 NHLBI NIH HHS

• Heat shock proteins
• Hsp70
• keloids

• Adolescent
• Adult
• Blotting, Western
• Collagen/drug effects
• Collagen/metabolism
• Female
• Fibroblasts/metabolism
• Gene Expression Regulation
• HSP70 Heat-Shock Proteins/genetics
• HSP70 Heat-Shock Proteins/metabolism
• HSP70 Heat-Shock Proteins/pharmacology
• Humans
• Keloid/drug therapy
• Keloid/genetics
• Keloid/metabolism
• Male
• RNA, Messenger/genetics
• RNA, Small Interfering/genetics
• Real-Time Polymerase Chain Reaction
• Transfection
• Up-Regulation

Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades a variety of extracellular matrix (ECM) components. In addition, MT1-MMP activates intracellular signaling through proteolysis-dependent and independent mechanisms. We have previously shown that binding of tissue inhibitor of metalloproteinases-2 (TIMP-2) to MT1-MMP controls cell proliferation and migration, as well as tumor growth in vivo by activating the Ras—extracellular signal regulated kinase-1 and -2 (ERK1/2) pathway through a mechanism that requires the cytoplasmic but not the proteolytic domain of MT1-MMP. Here we show that in MT1-MMP expressing cells TIMP-2 also induces rapid and sustained activation of AKT in a dose- and time-dependent manner and by a mechanism independent of the proteolytic activity of MT1-MMP. Fibroblast growth factor receptor-1 mediates TIMP-2 induction of ERK1/2 but not of AKT activation; however, Ras activation is necessary to transduce the TIMP-2-activated signal to both the ERK1/2 and AKT pathways. ERK1/2 and AKT activation by TIMP-2 binding to MT1-MMP protects tumor cells from apoptosis induced by serum starvation. Conversely, TIMP-2 upregulates apoptosis induced by three-dimensional type I collagen in epithelial cancer cells. Thus, TIMP-2 interaction with MT1-MMP provides tumor cells with either pro- or anti-apoptotic signaling depending on the extracellular environment and apoptotic stimulus.

• Apoptosis
• Cell Line, Tumor
• Humans
• Matrix Metalloproteinase 14/metabolism
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Interaction Maps
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, Fibroblast Growth Factor/metabolism
• Signal Transduction
• Tissue Inhibitor of Metalloproteinase-2/metabolism

• P30 CA016087 NCI NIH HHS
• R01 CA136715 NCI NIH HHS
• 3R01CA136715-03S1 NCI NIH HHS
• R01 CA136715-0101 NCI NIH HHS

Inflammatory processes are implicated in many diseases of the vasculature and have been shown to play a key role in the formation of intracranial aneurysms (IAs). Although the specific mechanisms underlying these processes have been thoroughly investigated in related pathologies, such as atherosclerosis, there remains a paucity of information regarding the immunopathology of IA. Cells such as macrophages and lymphocytes and their effector molecules have been suggested to be players in IA, but their specific interactions and the role of other components of the inflammatory response have yet to be determined. Drawing parallels between the pathogenesis of IA and other vascular disorders could provide a roadmap for developing a mechanistic understanding of the immunopathology of IA and uncovering useful targets for therapeutic intervention. Future research should address the presence and function of leukocyte subsets, mechanisms of leukocyte recruitment and activation, and the role of damage-associated molecular patterns in IA.

The corneal epithelium provides a protective barrier against pathogen entrance and abrasive forces, largely due to the intercellular junctional complexes between neighboring cells. After a prescribed duration at the corneal surface, tight junctions between squamous surface cells must be disrupted to enable them to desquamate as a component of the tissue homeostatic renewal. We hypothesize that matrix metalloproteinase (MMPs) are secreted by corneal epithelial cells and cleave intercellular junctional proteins extracellularly at the epithelial surface. The purpose of this study was to examine the expression of specific MMPs and tight junction proteins during both the light and dark phases of the circadian cycle, and to assess their temporal and spatial relationships in the Xenopus laevis corneal epithelium.

Expression of MMP-2, tissue inhibitor of MMP-2 (TIMP-2), membrane type 1-MMP (MT1-MMP) and the tight junction proteins occludin and claudin-4 were examined by confocal double-label immunohistochemistry on corneas obtained from Xenopus frogs at different circadian times. Occludin and claudin-4 expression was generally uniformly intact on the surface corneal epithelial cell lateral membranes during the daytime, but was frequently disrupted in small clusters of cells at night. Concomitantly, MMP-2 expression was often elevated in a mosaic pattern at nighttime and associated with clusters of desquamating surface cells. The MMP-2 binding partners, TIMP-2 and MT1-MMP were also localized to surface corneal epithelial cells during both the light and dark phases, with TIMP-2 tending to be elevated during the daytime.

MMP-2 protein expression is elevated in a mosaic pattern in surface corneal epithelial cells during the nighttime in Xenopus laevis, and may play a role in homeostatic surface cell desquamation by disrupting intercellular junctional proteins. The sequence of MMP secretion and activation, tight junction protein cleavage, and subsequent surface cell desquamation and renewal may be orchestrated by nocturnal circadian signals.

• Animals
• Circadian Rhythm
• Claudin-4/metabolism
• Epithelium, Corneal/metabolism
• Epithelium, Corneal/pathology
• Immunohistochemistry
• Matrix Metalloproteinase 14/metabolism
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinases/metabolism
• Microscopy, Confocal
• Occludin/metabolism
• Tight Junctions/metabolism
• Tight Junctions/pathology
• Tissue Inhibitor of Metalloproteinase-2/metabolism
• Xenopus laevis/metabolism

• R01 EY021497 NEI NIH HHS
• EY021497 NEI NIH HHS

• anti-TACE antibody
• exosite
• immunoreactivity
• phage-display randomization libraries
• sub-nanomolar affinity

Matrix metalloproteinases (MMPs) and, especially membrane type 1 (MT1)-MMP/MMP-14, are promising drug targets in malignancies. In contrast with multiple small-molecule and protein pan-inhibitors of MT1–MMP cleavage activity, the murine 9E8 monoclonal antibody targets the MMP-2-activating function of cellular MT1–MMP alone, rather than the general proteolytic activity and the pro-migratory function of MT1–MMP. Furthermore, the antibody does not interact in any detectable manner with other members of the membrane type (MT)-MMP family. The mechanism of this selectivity remained unknown. Using mutagenesis, binding and activity assays, and modeling in silico, we have demonstrated that the 9E8 antibody recognizes the MT-loop structure, an eight residue insertion that is specific for MT–MMPs and that is distant from the MT1–MMP active site. The binding of the 9E8 antibody to the MT-loop, however, prevents tissue inhibitor of metalloproteinases-2 (TIMP-2) association with MT1–MMP. As a result, the 9E8 antibody incapacitates the TIMP-2-dependent MMP-2-activating function alone rather than the general enzymatic activity of human MT1–MMP. The specific function of the 9E8 antibody we determined directly supports an essential, albeit paradoxical, role of the protein inhibitor (TIMP-2) in MMP-2 activation via a unique membrane-tethered mechanism. In this mechanism, the formation of a tri-molecular MT1–MMPTIMP-2MMP-2 complex is required for both the capture of the soluble MMP-2 proenzyme by cells and then its well-controlled conversion into the mature MMP-2 enzyme. In sum, understanding of the structural requirements for the 9E8 antibody specificity may pave the way for the focused design of the inhibitory antibodies against other individual MMPs.

• loose arthroplasty endoprostheses
• periprosthetic tissues
• soluble membrane type 1 matrix metalloproteinase
• tissue inhibitor of matrix metalloproteinases-2

CD44, MT1-MMP, and MMP9 are implicated in the migration of osteoclast and bone resorption. This study was designed to determine the functional relationship between CD44 and MT1-MMP in the activation of pro-MMP9. We used osteoclasts isolated from wild-type and CD44-null mice. Results showed that MT1-MMP is present in multiple forms with a molecular mass ~63, 55, and 45 kDa in the membrane of wild-type osteoclasts. CD44-null osteoclasts demonstrated a 55 kDa active MT1-MMP form in the membrane and conditioned medium. It failed to activate pro-MMP9 because TIMP2 binds and inhibits this MT1-MMP (~55 kDa) in CD44-null osteoclasts. The role of MT1-MMP in the activation of pro-MMP9, CD44 expression, and migration was confirmed by knockdown of MT1-MMP in wild-type osteoclasts. Although knockdown of MMP9 suppressed osteoclast migration, it had no effects on MT1-MMP activity or CD44 expression. These results suggest that CD44 and MT1-MMP are directly or indirectly involved in the regulation of pro-MMP9 activation. Surface expression of CD44, membrane localization of MT1-MMP, and activation of pro-MMP9 are the necessary sequence of events in osteoclast migration.

• polypeptide n-acetylgalactosaminyltransferase 2
• gastric cancer
• metastasis
• matrix metalloproteinase-2
• transforming growth factor-β1

• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Matrix Metalloproteinase 14/genetics
• Matrix Metalloproteinase 14/metabolism
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• N-Acetylgalactosaminyltransferases/genetics
• N-Acetylgalactosaminyltransferases/metabolism
• N-Acetylgalactosaminyltransferases/physiology
• Stomach Neoplasms
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Polypeptide N-acetylgalactosaminyltransferase

• extracellular matrix
• metalloproteinases
• fallopian tubes
• menstrual cycle

• Adult
• Computational Biology
• Extracellular Matrix Proteins/biosynthesis
• Fallopian Tubes/metabolism
• Female
• Humans
• Matrix Metalloproteinase 2/biosynthesis
• Matrix Metalloproteinase 9/biosynthesis
• Matrix Metalloproteinases/biosynthesis
• Menstrual Cycle/metabolism
• Transcriptome

• 090301 Wellcome Trust

• Cell Line
• Enzyme-Linked Immunosorbent Assay
• Extracellular Matrix/enzymology
• Feedback
• Humans
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Neovascularization, Physiologic
• Tissue Inhibitor of Metalloproteinase-2/biosynthesis