Ubiquitination in Periodontal Disease: A Review
Abstract
:1. Introduction
2. Periodontal Disease
3. Bacterial Pathogens of Periodontal Disease
4. Ubiquitination in Periodontal Disease
5. Future Directions for Periodontal Research
6. Conclusions
Acknowledgments
Conflicts of Interest
References
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Authors | Research Object (Bacteria, Cell, Fluid, or Tissues) | Methodolgy | Essence of a Discourse or Summary of Results | Reference |
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Maekawa, et al., 2014 | Porphyromonas gingivalis, Human neutrophils | Innate pattern recognition of P.g is predominantly mediated by TLR2, which synergizes with C5aR during periodontal inflammation. The authors examined Pg interactions with both C5aR and TLR2 using knockout mice and specific inhibitors. | Porphyromonas gingivalis (P.g)-induced co-activation of toll-like receptor 2 (TLR2) and the C5a receptor (C5aR) in neutorophils; the resulting crosstalk leads to ubiqutination and proteasomal degradation of MyD88, thereby inhibiting a host-protective antimicrobial response. This activity requires the C5aR/TLR2- dependent release of transforming growth factor-β1, which mediates ubiquitin-proteasome degradation of MyD88 via the E3 ubiqutin ligase Smad ubiquitin regulatory factor 1. MyD88 is unlikely to contribute to immune evasion mediated by the P.g-induced C5a-TLR2 crosstalk; however, it contributes to P.g infection clearance. | [52] |
Cai et al., 2016 | Porphyromonas gingivalis | P.g.-exposed macrophages were treated with 10 μg/mL MDP (MDP-low) up-regulated TNF-α by 29%, while 100 μg/mL or higher (MDP-high) significantly decreased the level of TNF-α (16–38%). | API activates the ubiquitin-editing enzyme A20 and restricts ubiquitination of nucleotide-binding oligomerization domain-containing protein 2, consequently inhibiting TNF-α secretion in response to P. gingivalis infection. | [53] |
Hong, et al., 2016 | Gingival tissues, Human periodontal ligament cell | The concentration of prostaglandin E2 was measured by a radioimmunoassay. Reverse transcription-polymerase chain reactions and Western blot analyses were used to measure the mRNA and protein levels, respectively. Osteoclastic differentiation was assessed in mouse bone marrow-derived macrophages using conditioned medium from LPS- and nicotine-treated hPDLCs. | The ubiquitin-edting protein A20 was upregulated in the gingival tissues and neutrophils of patients with periodontal disease and in LPS-exposed human periodontal ligament cells. | [56] |
Tsuchida, et al., 2016 | Gingival crevicular fluid | The authors explored the considerable variation in the molecular weights of protein bands using on-membrane digestion and liquid chromatography-tandem mass spectrometry (LC–MS/MS) analyses. In immunoprecipitation experiments, ubiquitin DCD was detected by Western blotting and by immunoprecipitation. | In immunoprecipitation experiments, ubiquitinated antimicrobial peptide dermcidin (DCD) in GCF was detected using Western blotting and immunoprecipitation with antibodies against DCD and mono-/poly-ubiquitinated proteins. | [58] |
Ghosh, et al., 2010 | Periodontal ligament cells | The authors used immunofluorescence, transfection assays, Western blotting, and ELISAs to show that p53 is degraded by a proteasome pathway in response to a proapoptotic disease-associated fibronectin fragment. | Investigated whether fibronectin fragments induce ubiqutination of p53 and its degradation by the proteasome. Inhibiting either the proteolytic function of the proteasome or suppressing ubiquitin at the protein level prevented degradation of p53 and subsequent apoptosis of primary periodontal ligament cells. | [59] |
Li, et al., 2012 | Keratocytic odontogenic tumors | They detected the expression of some key autophagy-related proteins in the clinical samples of keratocystic odontogenic tumors (KCOT) and radicular cysts and compared them via real-time quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis, respectively. The correlation between the tested autophagy-related proteins with cell antiapoptotic (Bcl-2) or proliferative (Ki-67) markers in KCOT was explored using a Spearman’s rank correlation, followed by a cluster analysis. | Evaluated the activation status of autophagy in keratocystic odontogenic tumors (KCOT) and detected and compared the expression patterns of some key autophagy-related proteins in clinical samples of KCOT and radicular cysts. Implicated the activation of autophagy in KCOT and showed a possible association with growth potential. | [60] |
Zeidán-Chuliá, et al., 2016 | Periodontitis-associated bacteria, Human oral neutrophils | Using systems biologytools, the authors aimed to: (1) identify an integrated interactome between matrix metallo proteinase (MMP)-REDOX/nitric oxide (NO) and apoptosis pathways upstream of periodontal inflammation; and (2) characterize the attendant topological network properties to uncover putative biomarkers to be tested in the saliva of patients with periodontitis. | Found Ubiqutin C (UBC), Jun proto-oncogene (JUN), and matrix metalloproteinase-14 (MMP-14) as the most central hub- and non-hub-bottlenecks among the 211 genes/proteins of the whole interactome. Described that UBC, JUN, and MMP-14 are likely an optimal candidate group of host-derived biomarkers, in combination with oral pathogenic bacteria-derived proteins, for detecting periodontitis in its early phase. | [61] |
Cai, et al., 2015 | Oral epidermis tissues and epithelial cells from the White sponge nevus patients | Sequence analysis of samples from a WSN Chinese family revealed a mutation (332 T > C) in the KRT13 gene that resulted in the amino acid change Leu111Pro. The pathological pathway behind the WSN expression profile was investigated using RNA sequencing (RNA-seq). | Investigated the pathogenesis of white sponge nevus (WSN), a rare periodontal hereditary disease, by expression profiling and found that the ribosome structure was damaged and the translation rate was limited in WSN patients, while ubiquitin-mediated proteolysis was enhanced. This study concluded that the abnormal degradation of keratin 13 protein in WSN patients may be associated with keratin 7 protein and an abnormal ubiquitination process. | [63] |
Jiang, et al., 2016 | Periodontal ligament cells and ameliorates experimental periodontitis in rats | hPDLCs were treated with lipopolysaccharide (LPS) and pretreated with bortezomib (BTZ). mRNA and protein levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, IL-6, and IL-8 were determined. The anti-inflammatory mechanism of BTZ was studied. Furthermore, experimental rat periodontitis was induced with ligature and LPS injection, and simultaneously and locally treated with BTZ (three injections/week). Four weeks after treatment, microcomputed tomography, immunohistochemistry, and histopathologic analyses were performed. | Bortezomib (BTZ) was the first proteasome inhibitor for clinical treatment of malignancies. The anti-cancer activity of BTZ is accompanied by an anti-inflammatory effect. Jiang et al., (2016) reported that in an LPS- and ligature-induced periodontal disease rat model, BTZ suppressed the expression of TNF-α, IL-1β, IL-6, and IL-8, reduced the ratio of receptor activation of RANKL/osteoprotegerin, and prevented alveolar bone resorption, suggesting that the anti-inflammatory activity of BTZ has a promising therapeutic effect against periodontal inflammatory responses in periodontal disease. | [65] |
Kitagaki, et al., 2015 | Periodontal ligament cells | A mouse PDL clone cell line, MPDL22, was cultured in mineralization medium in the presence or absence of bortezomib. The expression of calcification-related genes and calcified-nodule formation was evaluated by real-time PCR and Alizarin Red staining, respectively. | Investigated whether BTZ can induce differentiation of PDL cells into hard tissue-forming cells and found that BTZ enhanced the expression of bone morphogenetic protein-2, which induces cytodifferentiation and mineralization of PDL cells. BTZ induced cytodifferentiation of PDL cells by enhancing the accumulation of B-catenin within the cytosol and nucleus, suggesting that BTZ may be efficacious for use in periodontal regeneration therapy. | [66] |
Yin, et al., 2007 | Fusobacterium nucleatum, Oral epipithelial cells | Human b-defensin-2 (hBD2) is expressed in normal oral tissue leading to the hypothesis that oral epithelial cells are in an activated state with respect to innate immune responses under normal in vivo conditions. To test this hypothesis, global gene expression was evaluated in GECs in response to stimulation by an F. nucleatum cell wall (FnCW) preparation and hBD2 peptide. FnCW treatment altered 829 genes, while hBD2 altered 209 genes (P,0.005, ANOVA). | F. nucleatum and its cell wall extracts induce the expression of human beta-defensin-2 (hBD2), an antimicrobial and immunomodulatory peptide, in cultured primary human gingival epithelial cells in vitro. F. nucleatum cell wall extracts upregulated the expression of multiple protease inhibitors and suppressed NF-κB function and the ubiquitin/proteasome system. Both F. nucleatum cell wall extracts and hBD2 upregulated genes that may enhance the gingival epithelial barrier. | [67] |
Shin et al., 2015 | Periodontal ligament cells | To assess the apoptotic effects of STZ on periodontal ligament cells (PDLs), they were treated with or without different concentrations of STZ. Qualitative estimation of apoptotic cell death was obtained via a live/dead assay. The expression levels of apoptosis-related proteins were evaluated by a Western blot analysis. | Streptozotocin (STZ, 2-deoxy-2-3(3-(methyl-3-nitrosoureid)-d-glucopyranose) treatment dramatically reduces Mcl-1 (which induces myeloid leukemia cell differentiation protein) expression in a proteasome-dependent manner, thereby suppressing the growth of PDL cells through the Bax/Bak apoptotic signaling pathway. STZ may play an important role in inducing PDL cell apoptosis as a potential direct inducer of periodontitis in an STZ-induced diabetic animal. | [69] |
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Tsuchida, S.; Satoh, M.; Takiwaki, M.; Nomura, F. Ubiquitination in Periodontal Disease: A Review. Int. J. Mol. Sci. 2017, 18, 1476. https://doi.org/10.3390/ijms18071476
Tsuchida S, Satoh M, Takiwaki M, Nomura F. Ubiquitination in Periodontal Disease: A Review. International Journal of Molecular Sciences. 2017; 18(7):1476. https://doi.org/10.3390/ijms18071476
Chicago/Turabian StyleTsuchida, Sachio, Mamoru Satoh, Masaki Takiwaki, and Fumio Nomura. 2017. "Ubiquitination in Periodontal Disease: A Review" International Journal of Molecular Sciences 18, no. 7: 1476. https://doi.org/10.3390/ijms18071476