-
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2024To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis...
OBJECTIVE
To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA).
METHODS
Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors.
RESULTS
Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005).
CONCLUSION
MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.
Topics: Humans; Lung Diseases, Interstitial; Arthritis, Rheumatoid; Male; Middle Aged; Female; Prospective Studies; Matrix Metalloproteinase 7; Aged; Cross-Sectional Studies; Incidence; Risk Factors; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Matrix Metalloproteinase 3; Prevalence; Cohort Studies; Matrix Metalloproteinases; United States; Proportional Hazards Models
PubMed: 38268499
DOI: 10.1002/art.42812 -
Journal of Crohn's & Colitis Mar 2024Intestinal fibrosis is a common complication in patients with inflammatory bowel disease [IBD], in particular Crohn's disease [CD]. Unfortunately, at present intestinal... (Review)
Review
Intestinal fibrosis is a common complication in patients with inflammatory bowel disease [IBD], in particular Crohn's disease [CD]. Unfortunately, at present intestinal fibrosis is not yet preventable, and cannot be treated by interventions other than surgical removal. Intestinal fibrosis is characterized by excessive accumulation of extracellular matrix [ECM], which is caused by activated fibroblasts and smooth muscle cells. Accumulation of ECM results from an imbalanced production and degradation of ECM. ECM degradation is mainly performed by matrix metalloproteinases [MMPs], enzymes that are counteracted by tissue inhibitors of MMPs [TIMPs]. In IBD patients, MMP activity [together with other protease activities] is increased. At the same time, CD patients have a generally lower MMP activity compared to ulcerative colitis patients, who usually do not develop intestinal strictures or fibrosis. The exact regulation and role[s] of these MMPs in fibrosis are far from understood. Here, we review the current literature about ECM remodelling by MMPs in intestinal fibrosis and their potential role as biomarkers for disease progression or druggable targets.
Topics: Humans; Intestines; Crohn Disease; Inflammatory Bowel Diseases; Fibrosis; Matrix Metalloproteinases
PubMed: 37878770
DOI: 10.1093/ecco-jcc/jjad178 -
Small (Weinheim An Der Bergstrasse,... May 2024The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating...
The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed.
Topics: Animals; Mice; Disease Progression; Hydrogels; Hypoxia; Matrix Metalloproteinase 13; Microspheres; Osteoarthritis; RAW 264.7 Cells; Reactive Oxygen Species
PubMed: 38054626
DOI: 10.1002/smll.202308599 -
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 -
Seminars in Ophthalmology Nov 2023Matrix metalloproteinases (MMPs) are important regulators of the extracellular matrix (ECM) and are involved in many stages of cellular growth and development. An... (Review)
Review
Matrix metalloproteinases (MMPs) are important regulators of the extracellular matrix (ECM) and are involved in many stages of cellular growth and development. An imbalance of MMP expression is also the basis of many diseases, including eye diseases, such as diabetic retinopathy (DR), glaucoma, dry eye, corneal ulcer, keratoconus. This paper describes the role of MMPs in the glaucoma and their role in the glaucomatous trabecular meshwork (TM), aqueous outflow channel, retina, and optic nerve (ON). This review also summarizes several treatments for glaucoma that target MMPs imbalance and suggests that MMPs may represent a viable therapeutic target for glaucoma.
Topics: Humans; Intraocular Pressure; Glaucoma; Trabecular Meshwork; Extracellular Matrix; Matrix Metalloproteinases; Aqueous Humor
PubMed: 37224230
DOI: 10.1080/08820538.2023.2211149 -
Cardiovascular Research May 2024Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients...
AIMS
Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification.
METHODS AND RESULTS
We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries in patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process.
CONCLUSION
These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD.
Topics: Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Matrix Metalloproteinase 3; Gene Deletion; Vascular Calcification; Disease Models, Animal; Muscle, Smooth, Vascular; Humans; Recombinant Proteins; Aorta; Gene Expression
PubMed: 38454645
DOI: 10.1093/cvr/cvae035 -
Biomedicine & Pharmacotherapy =... Feb 2024Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature... (Review)
Review
Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature is the massive deposition of extracellular matrix (mainly collagen), eventually leading to tissue dysfunction and organ failure. The progression of fibrotic diseases has put a significant strain on global health and the economy, and as a result, there is an urgent need to find some new therapies. Previous studies have identified that inflammation, oxidative stress, some cytokines, and remodeling play a crucial role in fibrotic diseases and are essential avenues for treating fibrotic diseases. Among them, matrix metalloproteinases (MMPs) are considered the main targets for the treatment of fibrotic diseases since they are the primary driver involved in ECM degradation, and tissue inhibitors of metalloproteinases (TIMPs) are natural endogenous inhibitors of MMPs. Through previous studies, we found that MMP-9 is an essential target for treating fibrotic diseases. However, it is worth noting that MMP-9 plays a bidirectional regulatory role in different fibrotic diseases or different stages of the same fibrotic disease. Previously identified MMP-9 inhibitors, such as pirfenidone and nintedanib, suffer from some rather pronounced side effects, and therefore, there is an urgent need to investigate new drugs. In this review, we explore the mechanism of action and signaling pathways of MMP-9 in different tissues and organs, hoping to provide some ideas for developing safer and more effective biologics.
Topics: Humans; Matrix Metalloproteinase 9; Fibrosis; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases; Inflammation; Extracellular Matrix; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors
PubMed: 38181715
DOI: 10.1016/j.biopha.2023.116116 -
Expert Review of Clinical Immunology May 2024Matrix metalloproteinases (MMPs) are a group of enzymes that are essential in maintaining extracellular matrix (ECM) homeostasis, regulating inflammation and tissue... (Review)
Review
INTRODUCTION
Matrix metalloproteinases (MMPs) are a group of enzymes that are essential in maintaining extracellular matrix (ECM) homeostasis, regulating inflammation and tissue remodeling. In chronic rhinosinusitis (CRS), the overexpression of certain MMPs can contribute to chronic nasal tissue inflammation, ECM remodeling, and tissue repair.
AREAS COVERED
This review provides a comprehensive overview of the biological characteristics and functions of the MMP family, particularly focusing on the expression and activity of MMPs in patients with CRS, and delves into their role in the pathogenesis of CRS and their potential as therapeutic targets.
EXPERT OPINION
MMPs are important in tissue remodeling and have been implicated in the pathophysiology of CRS. Previous studies have shown that the expression of MMPs is upregulated in the nasal mucosa of patients with CRS and positively correlates with the severity of CRS. However, there is still a large gap in the research content of MMP in CRS, and the specific expression and pathogenic mechanism of MMP still need to be clarified. The significance and value of the ratio of MMP to tissue inhibitors of metalloproteinase (TIMP) in diseases still need to be demonstrated. Moreover, further studies are needed to assess the efficacy and safety of biologics that target MMPs in patients with CRS.
Topics: Humans; Rhinosinusitis; Nasal Polyps; Sinusitis; Inflammation; Chronic Disease; Matrix Metalloproteinases
PubMed: 38251631
DOI: 10.1080/1744666X.2024.2302362 -
Acta Biochimica Polonica Sep 2023The aim of this review is to specify new potential reliable and non-invasive methods for the diagnosis of biliary atresia (BA) that could shorten the way to diagnose BA,... (Review)
Review
The aim of this review is to specify new potential reliable and non-invasive methods for the diagnosis of biliary atresia (BA) that could shorten the way to diagnose BA, and finally the surgical treatment. Apart from the biomarkers that have been proven helpful and are used nowadays in neonatal wards, there are several new potential biomarkers that researchers have found to be helpful in the diagnosis of biliary atresia. Circulating microRNAs, matrix metalloproteinase-7, stool proteins, interleukin-33, Th17-associated cytokines, urinary metabolomics, anti-smooth muscle antibodies, heat shock proteins 90 and positive biliary epithelial cells CD56 are among those presented in this summary. These markers may play a new significant role in BA diagnosis. The described methods include Nomogram, Circulating microRNAs (miRNAs), Matrix metalloproteinase-7 (MMP-7), Stool proteins, Interleukin-33 (IL-33), Th17-associated cytokines, Alpha-aminoadipic acid and N-acetyl-d-mannosamine in urine, Anti-smooth muscle antibodies (ASMA), Heat shock proteins 90 (HSP90), Positive biliary epithelial cells CD56.
Topics: Infant, Newborn; Humans; Biliary Atresia; HSP90 Heat-Shock Proteins; Interleukin-33; Matrix Metalloproteinase 7; Autoantibodies; Biomarkers; Cytokines; MicroRNAs
PubMed: 37717264
DOI: 10.18388/abp.2020_6858 -
Molecules (Basel, Switzerland) Jul 2023Matrix metalloproteinases (MMPs) are zinc-dependent metalloproteinases that play important roles in a variety of diseases, including cancer, cardiovascular disease,... (Review)
Review
Matrix metalloproteinases (MMPs) are zinc-dependent metalloproteinases that play important roles in a variety of diseases, including cancer, cardiovascular disease, diabetes, obesity, and brain diseases. Dietary polyphenols are thought to have a variety of beneficial effects on these diseases characterized by inflammation. Clinical studies have demonstrated that MMPs are in most cases upregulated in various inflammatory diseases, including osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimer's disease. Studies using patient-derived human samples, animal studies, and cellular experiments have suggested that polyphenols may be beneficial against inflammatory diseases by suppressing MMP gene expression and enzyme activity. One important mechanism by which polyphenols exert their activity is the downregulation of reactive oxygen species that promote MMP expression. Another important mechanism is the direct binding of polyphenols to MMPs and their inhibition of enzyme activity. Molecular docking analyses have provided a structural basis for the interaction between polyphenols and MMPs and will help to explore new polyphenol-based drugs with anti-inflammatory properties.
Topics: Animals; Humans; Molecular Docking Simulation; Polyphenols; Antioxidants; Anti-Inflammatory Agents; Matrix Metalloproteinases
PubMed: 37513300
DOI: 10.3390/molecules28145426