Involvement of MT1-MMP and TIMP-2 in human periodontal disease

Oyarzún, Alejandro; Arancibia, Rodrigo; Hidalgo, Rodrigo; Peñafiel, Cristian; Cáceres, Mónica; Mj, González; Martı́nez, Jorge; Ph, Smith

doi:10.1111/j.1601-0825.2009.01651.x

Cited by 22 publications

(16 citation statements)

References 41 publications

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“…Tissue inhibitor of metalloproteinase 1 (TIMP1), an MMP inhibitor, was also up-regulated at 6 h by 2.1-fold. A large body of evidence demonstrates elevated levels of MMPs in periodontal disease compared to health [81]–[85]. Furthermore, there a positive correlation is revealed clinically between the levels of P. gingivalis detected in active sites and MMP13 levels [86].…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Bone Marrow Stromal Cells in Response to Porphyromonas gingivalis Secreted Products

Reddi

Belibasakis

2012

PLoS ONE

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Periodontitis is an infectious inflammatory disease that destroys the tooth-supporting (periodontal) tissues. Porphyromonas gingivalis is an oral pathogen highly implicated in the pathogenesis of this disease. It can exert its effects to a number of cells, including osteogenic bone marrow stromal cells which are important for homeostastic capacity of the tissues. By employing gene microarray technology, this study aimed to describe the overall transcriptional events (>2-fold regulation) elicited by P. gingivalis secreted products in bone marrow stromal cells, and to dissect further the categories of genes involved in bone metabolism, inflammatory and immune responses. After 6 h of challenge with P. gingivalis, 271 genes were up-regulated whereas 209 genes were down-regulated, whereas after 24 h, these numbers were 259 and 109, respectively. The early (6 h) response was characterised by regulation of genes associated with inhibition of cell cycle, induction of apoptosis and loss of structural integrity, whereas the late (24 h) response was characterised by induction of chemokines, cytokines and their associated intracellular pathways (such as NF-κB), mediators of connective tissue and bone destruction, and suppression of regulators of osteogenic differentiation. The most strongly up-regulated genes were lipocalin 2 (LCN2) and serum amyloid A3 (SAA3), both encoding for proteins of the acute phase inflammatory response. Collectively, these transcriptional changes elicited by P. gingivalis denote that the fundamental cellular functions are hindered, and that the cells acquire a phenotype commensurate with propagated innate immune response and inflammatory-mediated tissue destruction. In conclusion, the global transcriptional profile of bone marrow stromal cells in response to P. gingivalis is marked by deregulated homeostatic functions, with implications in the pathogenesis of periodontitis.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Bone Marrow Stromal Cells in Response to Porphyromonas gingivalis Secreted Products

Reddi

Belibasakis

2012

PLoS ONE

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“…It was shown to be increased in periodontitis‐affected gingival tissues when compared with healthy gingiva. Immunohistochemistry demonstrated the expression of matrix metalloproteinase‐24 in fibroblasts and macrophages that were in close association with the gingival collagen matrix .…”

Section: Role Of Epithelial‐derived Matrix Metalloproteinases In Perimentioning

confidence: 99%

Epithelial barrier and oral bacterial infection

Groeger¹,

Meyle²

2015

Periodontology 2000

161

140

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The oral epithelial barrier separates the host from the environment and provides the first line of defense against pathogens, exogenous substances and mechanical stress. It consists of underlying connective tissue and a stratified keratinized epithelium with a basement membrane, whose cells undergo terminal differentiation resulting in the formation of a mechanically resistant surface. Gingival keratinocytes are connected by various transmembrane proteins, such as tight junctions, adherens junctions and gap junctions, each of which has a specialized structure and specific functions. Periodontal pathogens are able to induce inflammatory responses that lead to attachment loss and periodontal destruction. A number of studies have demonstrated that the characteristics of pathogenic oral bacteria influence the expression and structural integrity of different cell-cell junctions. Tissue destruction can be mediated by host cells following stimulation with cytokines and bacterial products. Keratinocytes, the main cell type in gingival epithelial tissues, express a variety of proinflammatory cytokines and chemokines, including interleukin-1alpha, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha. Furthermore, the inflammatory mediators that may be secreted by oral keratinocytes are vascular endothelial growth factor, prostaglandin E2 , interleukin-1 receptor antagonist and chemokine (C-C motif) ligand 2. The protein family of matrix metalloproteinases is able to degrade all types of extracellular matrix protein, and can process a number of bioactive molecules. Matrix metalloproteinase activities under inflammatory conditions are mostly deregulated and often increased, and those mainly relevant in periodontal disease are matrix metalloproteinases 1, 2, 3, 8, 9, 13 and 24. Viral infection may also influence the epithelial barrier. Studies show that the expression of HIV proteins in the mucosal epithelium is correlated with the disruption of epithelial tight junctions, suggesting a possible enhancement of human papilloma virus infection by HIV-associated disruption of tight junctions. Altered expression of matrix metalloproteinases was demonstrated in keratinocytes transformed with human papilloma virus-16 or papilloma virus-18,. To summarize, the oral epithelium is able to react to a variety of exogenous, possibly noxious influences.

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“…These systemic effects have been attributed to either direct bacterial invasion or modulation of specific host inflammatory and tissue destructive mediators (Williams et al, 2008). ity of MMP-2 is dependent on the balance between MT1-MMP/ TIMP-2 (Hernandez-Barrantes, Shimura, Soloway, Sang, & Fridman, 2001;Oyarzun et al, 2010;Shofuda et al, 1998). This mechanism of MMP-2 activation by an MT1-MMP-TIMP-2 complex has been well recognised in other systems (Butler et al, 1998;Kinoshita et al, 1998;Strongin et al, 1995).…”

Section: Introductionmentioning

confidence: 97%

“…Extracellular MMP activities are controlled by the blockage of autolytic MMP activation or by endogenous proteinase inhibitors, such as tissue inhibitors of MMPs (TIMPs) (Nagase et al , 2006, Brew et al , 2010). Regulation of the proteolytic activity of MMP-2 is dependent on the balance between MT1-MMP/TIMP-2 (Shofuda et al , 1998, Hernandez-Barrantes et al , 2001, Oyarzun et al , 2010). This mechanism of MMP-2 activation by an MT1-MMP–TIMP-2 complex has been well recognized in other systems (Strongin et al , 1995, Butler et al , 1998, Kinoshita et al , 1998).…”

Section: Introductionmentioning

confidence: 99%

Treponema denticolaincreases MMP-2 expression and activation in the periodontium via reversible DNA and histone modifications

Ateia

Sutthiboonyapan

Kamarajan

et al. 2018

Cellular Microbiology

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Host-derived matrix metalloproteinases (MMPs) and bacterial proteases mediate destruction of extracellular matrices and supporting alveolar bone in periodontitis. The Treponema denticola dentilisin protease induces MMP-2 expression and activation in periodontal ligament (PDL) cells, and dentilisin-mediated activation of pro-MMP-2 is required for cellular fibronectin degradation. Here, we report that T. denticola regulates MMP-2 expression through epigenetic modifications in the periodontium. PDL cells were treated with epigenetic enzyme inhibitors before or after T. denticola challenge. Fibronectin fragmentation, MMP-2 expression, and activation were assessed by immunoblot, zymography, and qRT-PCR, respectively. Chromatin modification enzyme expression in T. denticola-challenged PDL cells and periodontal tissues were evaluated using gene arrays. Several classes of epigenetic enzymes showed significant alterations in transcription in diseased tissue and T. denticola-challenged PDL cells. T. denticola-mediated MMP-2 expression and activation were significantly reduced in PDL cells treated with inhibitors of aurora kinases and histone deacetylases. In contrast, DNA methyltransferase inhibitors had little effect, and inhibitors of histone acetyltransferases, methyltransferases, and demethylases exacerbated T. denticola-mediated MMP-2 expression and activation. Chronic epigenetic changes in periodontal tissues mediated by T. denticola or other oral microbes may contribute to the limited success of conventional treatment of chronic periodontitis and may be amenable to therapeutic reversal.

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Involvement of MT1-MMP and TIMP-2 in human periodontal disease

Abstract: Our observations show an increased expression of MT1-MMP and TIMP-2 in periodontitis-affected gingival tissues. The altered balance between these two molecular mediators of collagen remodeling suggests their involvement in human periodontal disease.

Cited by 22 publications

References 41 publications

Transcriptional Profiling of Bone Marrow Stromal Cells in Response to Porphyromonas gingivalis Secreted Products

Transcriptional Profiling of Bone Marrow Stromal Cells in Response to Porphyromonas gingivalis Secreted Products

Epithelial barrier and oral bacterial infection

Treponema denticolaincreases MMP-2 expression and activation in the periodontium via reversible DNA and histone modifications

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