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![Matrix metalloproteinase (MMP) activation cascades in connective tissue catabolism during periodontitis. Full and partial circles with their respective number represent latent and activated specific MMPs. Brown T bars represent collagen fibers. (A) Tooth and its supporting structures: radicular cement, periodontal ligament (PL), and alveolar bone. (B) Membrane-bounded MMP-14 activates proMMP-13 to degrade type I collagen, which constitutes the bulk component of radicular cement, periodontal ligament (PL), and alveolar bone extracellular matrix; MMP-13 activates proMMP-9, which in turn might activate proMMP-2 and proMMP-13. MMP-2 and MMP-9 further process the gelatin resulting from collagenase activity. MMP-13 can undergo autoactivation by selfproteolysis. Reactive oxygen species, such as HOCl and H 2 O 2 , from phagocytes, can also modify the proteases/antiproteases balance, activating latent MMPs and inactivating the tissue inhibitor of MMP (TIMP)-1. MPO, myeloperoxidase [8].](publication/342791984/figure/fig1/AS:911190544904192@1594256163813/Matrix-metalloproteinase-MMP-activation-cascades-in-connective-tissue-catabolism-during.png)
Matrix metalloproteinase (MMP) activation cascades in connective tissue catabolism during periodontitis. Full and partial circles with their respective number represent latent and activated specific MMPs. Brown T bars represent collagen fibers. (A) Tooth and its supporting structures: radicular cement, periodontal ligament (PL), and alveolar bone. (B) Membrane-bounded MMP-14 activates proMMP-13 to degrade type I collagen, which constitutes the bulk component of radicular cement, periodontal ligament (PL), and alveolar bone extracellular matrix; MMP-13 activates proMMP-9, which in turn might activate proMMP-2 and proMMP-13. MMP-2 and MMP-9 further process the gelatin resulting from collagenase activity. MMP-13 can undergo autoactivation by selfproteolysis. Reactive oxygen species, such as HOCl and H 2 O 2 , from phagocytes, can also modify the proteases/antiproteases balance, activating latent MMPs and inactivating the tissue inhibitor of MMP (TIMP)-1. MPO, myeloperoxidase [8].
Source publication
This review provides a detailed description of matrix metalloproteinases (MMPs), focusing on those that are known to have critical roles in bone and periodontal disease. Periodontal disease is an inflammatory process initiated by anaerobic bacteria, which promote the host immune response in the form of a complex network of molecular pathways involv...
Context in source publication
Context 1
... a number of MMPs have been described in gingival tissues (such as MMP-2, MMP-7, and MMP-14) [26], the most widely reported MMPs in gingival crevicular fluid (GCF) are MMP-8, MMP-9, and MMP-13 [27][28][29][30], and among the three collagenases (MMP-1, MMP-8, and MMP-13), MMP-8 accounts for 80% of the total collagenase protein found in the GCF, with smaller relative amounts of MMP-13 and MMP-1 in chronic periodontitis [31]. In particular, the active MMP-8 (aMMP-8, collagenase-2) derived from neutrophils is known to be the main host-cell-derived collagenase that leads to periodontal tissue destruction as a result of the degradation of gingival and periodontal ligament collagen [32,33] (Figure 1, [8]). ...
Citations
... Degranulation is one of the ways in which neutrophils exert their anti-microbial and immunomodulatory functions and is important for the progression of periodontitis. The granules are also involved in the inflammatory response and destruction of periodontal tissues through the release of matrix metalloproteinases (MMPs) that break down the extracellular matrix (32) or elastase that disrupts the periodontal epithelial barrier through the cleavage of cell adhesion molecules (33). ...
Periodontal disease is a chronic inflammatory condition that affects the supporting structures of the teeth, including the periodontal ligament and alveolar bone. Periodontal disease is due to an immune response that stimulates gingivitis and periodontitis, and its systemic consequences. This immune response is triggered by bacteria and may be modulated by environmental conditions such as smoking or systemic disease. Recent advances in single cell RNA-seq (scRNA-seq) and in vivo animal studies have provided new insight into the immune response triggered by bacteria that causes periodontitis and gingivitis. Dysbiosis, which constitutes a change in the bacterial composition of the microbiome, is a key factor in the initiation and progression of periodontitis. The host immune response to dysbiosis involves the activation of various cell types, including keratinocytes, stromal cells, neutrophils, monocytes/macrophages, dendritic cells and several lymphocyte subsets, which release pro-inflammatory cytokines and chemokines. Periodontal disease has been implicated in contributing to the pathogenesis of several systemic conditions, including diabetes, rheumatoid arthritis, cardiovascular disease and Alzheimer’s disease. Understanding the complex interplay between the oral microbiome and the host immune response is critical for the development of new therapeutic strategies for the prevention and treatment of periodontitis and its systemic consequences.
... Matrix metalloproteinases (MMPs) in GCF, crucial for tissue remodeling, offer another layer of diagnostic potential. MMP-8, for instance, stands out as a reliable indicator of periodontal disease [100,101]. Furthermore, GCF contains markers of bone remodeling, such as RANKL and OPG, which provide insights into alveolar bone turnover, a critical aspect of periodontal disease progression. ...
Periodontal diseases represent a spectrum of gingival disorders with multifaceted etiologies. Identifying and utilizing biomarkers in these conditions are essential for early detection, risk stratification, and personalized therapeutic interventions. This chapter provides a comprehensive overview of biomarker research in gingival diseases, emphasizing clinical applications, detection methods, and the potential of saliva and gingival crevicular fluid as diagnostic vehicles. We also delve into emerging research areas such as microbiome-associated, epigenetic, and metagenomic biomarkers. The chapter underscores the challenges associated with biomarker validation, the promise of multi-marker panels for improved accuracy, and the potential of longitudinal studies to predict disease progression. As point-of-care technologies and wearables pave the way for future diagnostics, innovative solutions like biosensors and micro-electro-mechanical systems (MEMS) are highlighted. This chapter encapsulates the importance of advancing biomarker discovery and its pivotal role in reshaping gingival disease management.
... [41,42] Pathological alterations in periodontitis tissues are dependent on intracellular signaling, which was created by these substances. [43][44][45][46][47][48][49][50][51][52][53][54] Inflammasomes are critical regulators of the innate immunological response to pathogens in chronic illnesses. [46,47] Recent studies have shown the importance of the "inflammasome" complex of nucleotide-binding polymerization domain-like receptors (NLR) combinations in the immunological response in periodontal tissues. ...
A BSTRACT
Inflammatory chemicals are released by the immune system in response to any perceived danger, including irritants and pathogenic organisms. The caspase activation and the response of inflammation are governed by inflammasomes, which are sensors and transmitters of the innate immune system. They have always been linked to swelling and pain. Research has mainly concentrated on the NOD-like protein transmitter 3 (NLRP3) inflammasome. Interleukin (IL)-1 and IL-18 are pro-inflammatory cytokines that are activated by the NOD-like antibody protein receptor 3 (NLRP3), which controls innate immune responses. The NLRP3 inflammasome has been associated with gum disease and other autoimmune inflammatory diseases in several studies. Scientists’ discovery of IL-1’s central role in the pathophysiology of numerous autoimmune disorders has increased public awareness of these conditions. The first disease to be connected with aberrant inflammasome activation was the autoinflammatory cryopyrin-associated periodic syndrome (CAPS). Targeted therapeutics against IL-1 have been delayed in development because their underlying reasons are poorly understood. The NLRP3 inflammasome has recently been related to higher production and activation in periodontitis. Multiple periodontal cell types are controlled by the NLRP3 inflammasome. To promote osteoclast genesis, the NLRP3 inflammasome either increases receptor-activator of nuclear factor kappa beta ligand (RANKL) synthesis or decreases osteoclast-promoting gene (OPG) levels. By boosting cytokines that promote inflammation in the periodontal ligament fibroblasts and triggering apoptosis in osteoblasts, the NLRP3 inflammasome regulates immune cell activity. These findings support further investigation into the NLRP3 inflammasome as a therapeutic target for the medical treatment of periodontitis. This article provides a short overview of the NLRP3 inflammatory proteins and discusses their role in the onset of autoinflammatory disorders (AIDs) and periodontitis.
... Dental diseases are initiated by anaerobic bacteria present in dental plaque, that initiates host response involving complex network of proinflammatory mediators like growth factors, cytokines, and matrix metalloproteinases (MMPs) [1]. During physiologic and pathologic processes, changes in extracellular matrix (ECM) are regulated by various protease enzymes i.e., aspartic proteinase, serine proteinase, cysteine proteinase and metalloproteinase. ...
Aims and objectives
To analyze anti-MMP mode of action of Quaternary Ammonium Silane (QAS, codenamed as k21) by binding onto specific MMP site using computational molecular simulation and Anti-Sortase A (SrtA) mode of action by binding onto specific site using computational molecular simulation.
Materials and methods
In silico Molecular Dynamics (MD) was used to determine the interactions of K21 inside the pocket of the targeted protein (crystal structure of fibroblast collagenase-1 complexed to a diphenyl-ether sulphone based hydroxamic acid; PDB ID: 966C; Crystal structure of MMP-2 active site mutant in complex with APP-derived decapeptide inhibitor. MD simulations were accomplished with the Desmond package in Schrödinger Drug Discovery Suite. Blood samples (~ 0.5 mL) collected into K2EDTA were immediately transferred for further processing using the Litron MicroFlow® PLUS micronucleus analysis kit for mouse blood according to the manufacturer’s instructions. Bacterial Reverse Mutation Test of K21 Molecule was performed to evaluate K21 and any possible metabolites for their potential to induce point mutations in amino acid-requiring strains of Escherichia coli (E. coli) (WP2 uvrA (tryptophan-deficient)).
Results
Molecular Simulation depicted that K21 has a specific pocket binding on various MMPs and SrtA surfaces producing a classical clouting effect. K21 did not induce micronuclei, which are the result of chromosomal damage or damage to the mitotic apparatus, in the peripheral blood reticulocytes of male and female CD-1 mice when administered by oral gavage up to the maximum recommended dose of 2000 mg/kg. The test item, K21, was not mutagenic to Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 uvrA in the absence and presence of metabolic activation when tested up to the limit of cytotoxicity or solubility under the conditions of the test.
Conclusion
K21 could serve as a potent protease inhibitor maintaining the physical and biochemical properties of dental structures.
... The lowest concentrations of TIMP-1 were observed in patients with periodontitis, and the concentrations increased after periodontal treatment. tissue repair process, this tissue damage can cause MMP expression to be increased [13]. Pathogens trigger the host immune system, resulting in an inflammatory reaction. ...
... Research should focus on multiple therapeutic options, including small molecule inhibitors, monoclonal antibodies, and nanoparticles, to improve periodontal health. Recent advancements include selective synthetic inhibitors designed for specific MMPs, such as synthetic cyclic peptide CTT (HWGFTLC), which appears to target gelatinases selectively [13]. Numerous innovative approaches are also being explored, ranging from TIMP analogs to function-blocking antibodies. ...
Matrix metalloproteinases (MMPs) are a diverse family of endopeptidases that play a pivotal role in tissue remodeling and extracellular matrix (ECM) degradation, including in the periodontium. These enzymes are implicated in various biological processes, such as inflammation, cell proliferation, and wound healing. MMPs also contribute to remodeling the Periodontal Ligament (PDL) and alveolar bone by degrading ECMw proteins, thereby releasing growth factors beneficial for cellular repair and differentiation. Their activity is finely regulated through gene expression, proenzyme activation, and inhibition by tissue inhibitors of MMPs (TIMPs). A balanced interplay between MMPs and TIMPs is crucial for maintaining tissue homeostasis. While MMPs have beneficial roles in tissue repair and cellular functions, their dysregulation can exacerbate inflammatory responses and compromise tissue integrity. This chapter explores the dual nature of MMPs in the periodontium, examining whether they serve as a boon or a bane in periodontal health.
... This innovative strategy would allow for the automatic adjustment of therapeutic dosages based on the severity of inflammation and MMP levels, thus optimizing the treatment outcomes. [100] In addition to considering the dosage, the precise activation locations for these bio-functional cargos (potent odontogenic growth factors and comprising anti-inflammatory drugs) are crucial. Traditional first-line anti-inflammatory medications primarily exert their effects within cells, whereas potent growth factors typically operate within the abundant ECM. ...
The quest for effective and reliable methods of delivering medications, with the aim of improving delivery of therapeutic agent to the intended location, has presented a demanding yet captivating field in biomedical research. The concept of smart drug delivery systems is an evolving therapeutic approach, serving as a model for directing drugs to specific targets or sites. These systems have been developed to specifically target and regulate the administration of therapeutic substances in a diverse array of chronic conditions, including periodontitis, diabetes, cardiac diseases, inflammatory bowel diseases, rheumatoid arthritis, and different cancers. Nevertheless, numerous comprehensive clinical trials are still required to ascertain both the immediate and enduring impacts of such nanosystems on human subjects. This review delves into the benefits of different drug delivery vehicles, aiming to enhance comprehension of their applicability in addressing present medical requirements. Additionally, it touches upon the current applications of these stimuli‐reactive nanosystems in biomedicine and outlines future development prospects.
... Many overlapping factors are involved in the maintenance and further development of periodontitis, including genetic and environmental determinants, the host immune response to inflammation, and behavioral factors. Various types of biological active compounds are involved in the complex pathomechanism of this disease, possibly including extracellular matrix metalloproteinases (MMPs) [5,7,[10][11][12]. ...
... Currently, there are attempts to use MMPs as markers of cancers such as breast cancer or cancers of the reproductive organs [16][17][18]. Some studies indicate that these enzymes can be considered as potential markers in the diagnosis of periodontitis and the prognosis of its development [11], and of particular interest in the field of periodontology is metalloproteinase 8 , which belongs to the group of collagenases. The aim of the present study was to gather current knowledge on the importance of MMP-8 in periodontitis and also the usefulness of this enzyme in the diagnosis of this condition. ...
Periodontitis is a complex condition. Left untreated, it leads to tooth loss and the need for prosthetic treatment. The incidence of periodontitis is steadily increasing, so new methods are being sought to aid in the diagnosis of the disease. Among the methods postulated is the determination of concentrations of bioactive compounds which include extracellular matrix metalloproteinases (MMPs). These enzymes are present in various structural elements of the stomatognathic system. The most promising enzyme of this group appears to be metalloproteinase 8 (MMP-8). MMP-8 assays are performed in gingival fluid or saliva, and MMP-8 levels have been shown to be higher in patients with periodontitis compared to healthy subjects and correlated with some clinical parameters of the condition and the severity of the disease. In addition, the preliminary usefulness of this enzyme in evaluating the effectiveness of periodontal treatment and doxycycline therapy has been demonstrated. Determination of the active form of MMP-8 (aMMP-8) in oral rinse fluid using off-the-shelf assays shows the highest potential. Despite reports about aMMP-8 and promising data on the role of MMP-8 in periodontal diagnosis, a clear determination of the usefulness of this enzyme requires further research.
... teeth, improper brushing techniques, accumulation of yellow plaque layer on teeth, poor oral hygiene & untreated gingival inflammation i.e. gingivitis leads to periodontitis.(Stepaniuk, 2019). In PD the inflammation is triggered by bacteria & secretion of inflammatory mediators such as cytokines, growth factors and matrix metalloproteinases (MMPs).(Checchi et al., 2020). In this disease, there is increased gingival redness, bleeding gums with swelling, presence of neutrophils & activation of the body defense against infection by increasing the pro-inflammatory mediators (Interleukin 1-beta, prostaglandins, tumor necrosis factor) and MMPs. MMPs are inhibited by the tissue inhibitors of Several studies r ...
Periodontitis is disorder of periodontium characterized by inflammation around teeth. Imbalance between matrix metalloprotienase8, tissue inhibitor of matrix metalloproteinase-1
... Multiple MMPs, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-13, are upregulated in gingival crevicular fluid during periodontitis [99]. While inhibition of MMPs using tetracyclines and their chemically modified variants (doxycycline, minocycline) limits periodontal tissue destruction, some MMP activity is needed for organized matrix deposition [100]. Optimizing the timing and dosage of MMP inhibitors is critical for balancing their protective and regenerative effects. ...
Gingival tissue engineering aims to regenerate damaged or diseased gingival tissues by applying biomaterials, growth factors, and stem cells. This chapter explores advancements and strategies in gingival tissue engineering. It begins by introducing the goals and anatomy/physiology of the gingiva. Biomaterial selection and design for gingival scaffolds and delivery methods for bioactive molecules to stimulate tissue growth are discussed. Stem cells are highlighted for their role in gingival regeneration - their isolation, characterization, and differentiation. Strategies like cell-based approaches, scaffold-free techniques, and hybrids combining cells, scaffolds, and growth factors are outlined. Preclinical and clinical studies assessing treatment safety/efficacy and methods to evaluate outcomes are reviewed. Challenges around improving cell viability, integration, and function are examined. Future directions focus on addressing these challenges. Ethical considerations and regulatory aspects are addressed to ensure responsible translation into clinical practice. This chapter provides insights into the current state and prospects of regenerative approaches in gingival tissue engineering, including their potential to impact gingival disease treatment and oral health promotion.
... investigated to understand their function in the pathogenesis of periodontitis [7]. There is a need to further identify the functions of other Matrix metalloproteinase (MMPs), especially MMP-7. ...
... However, other MMPs, such as MMP-8, MMP-9, and MMP-13, have established roles as biomarkers for the development and detection of periodontitis [7]. Yet, a group of biomarkers will probably be more accurate than a single one. ...
Context
MMP-7 supports the immune response and can have both beneficial and destructive effects. As part of the innate host defense, MMP-7 is connected to the mucosal antimicrobial defense. Even though research on other Matrix metalloproteinase (MMPs) is well-established, understanding MMP-7 expression is required to establish an improved diagnostic strategy.
Aims
This research investigates the mRNA expression of MMP-7 and RANKL by RT-qPCR assay.
Methods and material
Twelve male Sprague Dawley rats were allocated into three groups, no treatment, experimental (7 and 14 days). Periodontitis is induced by sterile wire insertion (0.2 mm) and Enterococcus faecalis inoculation within the gingival sulcus situated between the maxillary right 1st and 2nd molar tooth regions. Following euthanasia, tissue samples from the maxillary gingiva and maxillary jaw were extracted for quantitative real-time PCR assay and histopathological assessment.
Results
Results showed that at 7 days, there was significant upregulation of MMP-7, which was downregulated in 14 days, as well as migration of the junctional epithelium, attachment loss, inflammatory cells, and fibroblasts, as observed by histological analysis.
Conclusions
Thus, the study suggests that MMP-7 is associated with the progression of periodontitis.
