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The FEBS Journal Jun 2023CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand...
CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand CD95L induces its oligomerization leading in turn to the transduction of either apoptotic or nonapoptotic signals. CD95L can exist as both membrane-anchored and soluble forms (sCD95L), the latter resulting from the proteolytic cleavage of the former. Candidate proteases able to achieve CD95L cleavage were identified as matrix metalloproteases (MMP) due to their demonstrated ability to cleave other TNF superfamily ligands. The main goal of this study was to systematically identify the MMP family members capable of cleaving CD95L and subsequently determine the corresponding cleavage sites. By using different orthogonal biochemical approaches and combining them with molecular modelling, we confirmed data from the literature regarding CD95L cleavage by MMP-3 and MMP-7. Moreover, we found that MMP-2 and MMP-12 can cleave CD95L and characterized their resulting cleavage sites. This study provides a systematic approach to analyse the cleavage of CD95L, which until now had only been poorly described.
Topics: Fas Ligand Protein; fas Receptor; Metalloproteases; Apoptosis
PubMed: 36694998
DOI: 10.1111/febs.16737 -
Biology of Sex Differences May 2023Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting...
INTRODUCTION
Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD.
METHODS
In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aβ and tau pathology as well as disease progression. Further, we studied sex-specific interactions.
RESULTS
MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aβ biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women.
CONCLUSION
Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.
Topics: Humans; Female; Male; Alzheimer Disease; Matrix Metalloproteinase 10; Matrix Metalloproteinase 3; Cross-Sectional Studies
PubMed: 37221606
DOI: 10.1186/s13293-023-00514-x -
Brain Research Bulletin Nov 2023The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders...
BACKGROUND
The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders (PND) is accompanied by the increased expression of MMP-2 and MMP-9 in the hippocampus. However, the effect of inhibiting MMP-2 and MMP-9 on PND is not clear. In this study we aimed to evaluate the effects of inhibiting MMP-2 and MMP-9 on cognitive function in the aged mice after surgery, in order to find a possible target for the prevention and treatment of PND METHODS: In this study, 14-month-old C57BL/6 mice were used to establish a PND model by tibial fracture surgery and sevoflurane anesthesia. Three days later, part of the mice were subjected to cognitive assessment and the other was sacrificed for biochemical analysis. We used the Novel object recognition test and Fear conditioning test to evaluate the postoperative cognitive function of mice. The expression of mmp-2 and MMP-9 was detected by western blotting. We also examined the expression of claudin-5 and occludin using Western blotting, and the activation of microglia and astrocytes using immunofluorescence.
RESULTS
The results showed that surgery increased the expression of MMP-2 and MMP-9 in the hippocampus of mice, accompanied by cognitive impairment, decreased expression of claudin-5 and occludin, and increased activation of microglia and astrocytes. However, inhibition of MMP-2 and MMP-9 expression by SB-3CT reversed these changes.
CONCLUSIONS
Our study shows that inhibition of MMP-2 and MMP-9 alleviates anesthesia/surgery-induced cognitive decline by increasing BBB integrity and inhibiting glial cell activation.
Topics: Animals; Mice; Blood-Brain Barrier; Claudin-5; Cognitive Dysfunction; Hippocampus; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Occludin
PubMed: 37939860
DOI: 10.1016/j.brainresbull.2023.110810 -
Viruses Sep 2022SARS-CoV-2 cell-cell fusion and syncytiation is an emerging pathomechanism in COVID-19, but the precise factors contributing to the process remain ill-defined. In this...
SARS-CoV-2 cell-cell fusion and syncytiation is an emerging pathomechanism in COVID-19, but the precise factors contributing to the process remain ill-defined. In this study, we show that metalloproteases promote SARS-CoV-2 spike protein-induced syncytiation in the absence of established serine proteases using cell-cell fusion assays. We also show that metalloproteases promote S2'-activation of the SARS-CoV-2 spike protein, and that metalloprotease inhibition significantly reduces the syncytiation of SARS-CoV-2 variants of concern. In the presence of serine proteases, however, metalloprotease inhibition does not reduce spike protein-induced syncytiation and a combination of metalloprotease and serine protease inhibition is necessitated. Moreover, we show that the spike protein induces metalloprotease-dependent ectodomain shedding of the ACE2 receptor and that ACE2 shedding contributes to spike protein-induced syncytiation. These observations suggest a benefit to the incorporation of pharmacological inhibitors of metalloproteases into treatment strategies for patients with COVID-19.
Topics: Humans; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Angiotensin-Converting Enzyme 2; COVID-19; Cell Fusion; Serine Endopeptidases; Metalloproteases; Serine Proteases
PubMed: 36298651
DOI: 10.3390/v14102094 -
Cells May 2020The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin... (Review)
Review
The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.
Topics: Animals; Clinical Trials as Topic; Disease; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Signal Transduction
PubMed: 32466129
DOI: 10.3390/cells9051313 -
Biochemical Society Transactions Apr 2021Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to... (Review)
Review
Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders - collectively termed the 'serpinopathies' - but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by 'omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues - as well as their dysregulation in OA - are explored.
Topics: Animals; Cartilage; Extracellular Matrix; Gene Expression Regulation; Humans; Metalloproteases; Multigene Family; Osteoarthritis; Protein Conformation; Serpins
PubMed: 33843993
DOI: 10.1042/BST20201231 -
Cell Communication and Signaling : CCS Mar 2023Metastasis is the main cause of death in patients with colorectal cancer (CRC). Apart from platelets, platelet-derived microparticles (PMPs) are also considered...
BACKGROUND
Metastasis is the main cause of death in patients with colorectal cancer (CRC). Apart from platelets, platelet-derived microparticles (PMPs) are also considered important factors that can modify the activity of cancer cells. PMPs are incorporated by cancer cells and can also serve as intracellular signalling vesicles. PMPs are believed to affect cancer cells by upregulating their invasiveness. To date, there is no evidence that such a mechanism occurs in colorectal cancer. It has been shown that platelets can stimulate metalloproteases (MMPs) expression and activity via the p38MAPK pathway in CRC cells, leading to their elevated migratory potential. This study aimed to investigate the impact of PMPs on the invasive potential of CRC cells of various phenotypes via the MMP-2, MMP-9 and p38MAPK axis.
METHODS
We used various CRC cell lines, including the epithelial-like HT29 and the mesenchymal-like SW480 and SW620. Confocal imaging was applied to study PMP incorporation into CRC cells. The presence of surface receptors on CRC cells after PMP uptake was evaluated by flow cytometry. Transwell and scratch wound-healing assays were used to evaluate cell migration. The level of C-X-C chemokine receptor type 4 (CXCR4), MMP-2, and MMP-9 and the phosphorylation of ERK1/2 and p38MAPK were measured by western blot. MMP activity was determined using gelatine-degradation assays, while MMP release was evaluated by ELISA.
RESULTS
We found that CRC cells could incorporate PMPs in a time-dependent manner. Moreover, PMPs could transfer platelet-specific integrins and stimulate the expression of integrins already present on tested cell lines. While mesenchymal-like cells expressed less CXCR4 than epithelial-like CRC cells, PMP uptake did not increase its intensity. No significant changes in CXCR4 level either on the surface or inside CRC cells were noticed. Levels of cellular and released MMP-2 and MMP-9 were elevated in all tested CRC cell lines after PMP uptake. PMPs increased the phosphorylation of p38MAPK but not that of ERK1/2. Inhibition of p38MAPK phosphorylation reduced the PMP-induced elevated level and release of MMP-2 and MMP-9 as well as MMP-dependent cell migration in all cell lines.
CONCLUSIONS
We conclude that PMPs can fuse into both epithelial-like and mesenchymal-like CRC cells and increase their invasive potential by inducing the expression and release of MMP-2 and MMP-9 via the p38MAPK pathway, whereas CXCR4-related cell motility or the ERK1/2 pathway appears to not be affected by PMPs. Video Abstract.
Topics: Humans; Cell-Derived Microparticles; Colorectal Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Signal Transduction; Neoplasm Invasiveness
PubMed: 36882818
DOI: 10.1186/s12964-023-01066-8 -
Arteriosclerosis, Thrombosis, and... Sep 2019
Topics: Disintegrins; Metalloproteases; Thrombospondin 1; Thrombospondins; von Willebrand Factor
PubMed: 31433699
DOI: 10.1161/ATVBAHA.119.313110 -
Cellular and Molecular Life Sciences :... Aug 2019This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of... (Review)
Review
This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.
Topics: Central Nervous System; Humans; Matrix Metalloproteinases; Metalloproteases; Neurodegenerative Diseases; Tissue Inhibitor of Metalloproteinases
PubMed: 31175371
DOI: 10.1007/s00018-019-03172-8 -
Biochimica Et Biophysica Acta.... Feb 2020Preeclampsia is a syndrome characterised by vascular dysfunction, impaired angiogenesis, and hypertension during pregnancy. Even when the precise pathophysiology of... (Review)
Review
Preeclampsia is a syndrome characterised by vascular dysfunction, impaired angiogenesis, and hypertension during pregnancy. Even when the precise pathophysiology of preeclampsia remains elusive, impaired vascular remodelling and placental angiogenesis in the placental villi and defective trophoblast invasion of the uterus are proposed as crucial mechanisms in this syndrome. Reduced trophoblast invasion leads to reduced uteroplacental blood flow and oxygen availability and increased oxidative stress. These phenomena trigger the release of soluble factors into the maternal and foetoplacental circulation that are responsible of the clinical features of preeclampsia. New blood vessels generation as well as vascular remodelling are mechanisms that require expression and activity of different proteases, including matrix metalloproteases, a-disintegrin and metalloproteases, and a-disintegrin and metalloprotease with thrombospondin motifs. These proteases exert proteolysis of the extracellular matrix. Additionally, cathepsins, a family of proteolytic enzymes, are primarily located in lysosomes but are also released by cells to the extracellular space. This review focuses on the role that these proteases play in the regulation of the uterine trophoblast invasion and the placental vascular remodelling associated with preeclampsia.
Topics: Female; Humans; Matrix Metalloproteinases; Oxidative Stress; Oxygen; Peptide Hydrolases; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts; Uterus; Vascular Remodeling
PubMed: 30954558
DOI: 10.1016/j.bbadis.2019.04.004