Anti‐inflammatory and anti‐osteoclastogenic effects of zinc finger protein <scp>A</scp>20 overexpression in human periodontal ligament cells

Hong, Ji Youn; Bae, Won Kyung; Yi, Jin-Kyu; Kim, G.-T.; Kim, E.-C.

doi:10.1111/jre.12332

Cited by 30 publications

(57 citation statements)

References 60 publications

(93 reference statements)

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“…Regarding missense variants, KRT25 and EEFSEC have never been directly associated with periodontitis, although some impact on tissue homeostasis, immune‐inflammatory cascade, and oxidative stress have been reported before . Otherwise, ZNF136 (a transcription factor family member) has never been directly associated with periodontitis, but other ZNF members were associated with destructive oral conditions . Interestingly, PPI network analysis showed that the missense variants in ZNF136 , KRT25 , and EEFSEC were linked to the same major node – UBC .…”

Section: Discussionmentioning

confidence: 96%

“…[34][35][36] Otherwise, ZNF136 (a transcription factor family member) has never been directly associated with periodontitis, but other ZNF members were associated with destructive oral conditions. 37,38 Interestingly, PPI network analysis showed that the missense variants in ZNF136, KRT25, and EEFSEC were linked to the same major node -UBC. This gene belongs to well-established biological processes in the pathogenesis of periodontitis, like the MAPK pathway, antigen processing and presentation via MHC-I, and apoptotic processes, and it was reported as an important gene for periodontitis in an interactome study, 39 what could represent an alteration in this pathway, leading to major risk for periodontal destruction.…”

Section: Discussionmentioning

confidence: 99%

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Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

Taiete

Casati

Martins

et al. 2019

Journal of Periodontology

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Background Aggressive periodontitis (AgP), currently periodontitis grade C, presents early onset, rapid progression, and a poorly established genetic association. Thus, this study aimed to identify genetic variants associated with AgP via whole exome sequencing (WES) through a familial screening approach. Methods WES was performed in two nuclear families, including a proband and a parent affected by AgP and an unaffected parent and sibling. Common variants among affected individuals, excluding those common to healthy people, from each family, composed the data set associated with AgP. In silico analysis evaluated the impact of each variant on protein structure and protein‐protein interactions. Moreover, identified deleterious variants were validated in a populational analysis (n = 96). Results The missense single nucleotide variations (SNVs) rs142548867 in EEFSEC (c.668C>T), rs574301770 in ZNF136 (c.466C>G), and rs72821893 in KRT25 (c.800G>A) and the frameshift indels rs37146475 in GPRC6A (c.2323‐2324insT) and c.1366_1372insGGAGCAG in ELN were identified in AgP and have a predicted functional impact on proteins. In silico analysis indicated that the indel in GPRC6A generates a loss of the C‐terminal tail of the Gprca protein. Furthermore, this SNV was significantly associated with AgP in a population‐based investigation. Conclusion Novel frameshift variation in GPRC6A (c.2323‐2324insT) was identified as a potential genetic alteration associated with AgP occurrence.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

Taiete

Casati

Martins

et al. 2019

Journal of Periodontology

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“…Hong et al found that A20 overexpression decreased the protein expression of nuclear p65, and the number of osteoclasts induced by LPS and nicotine . It indicates that A20 overexpression inhibited NF‐κB pathway and osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16] Many studies have reported that A20 overexpression in human periodontal ligament cells (hPDLCs) decreases RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs) and that A20 can inhibit autophagy through limiting the K63-linkage ubiquitination of TRAF6, or by directly deubiquitinating Beclin1. 17,18 Numerous studies have shown that periodontal tissues are in a hypoxic microenvironment during periodontitis. 19 The hypoxic condition selected in this study closely resembled that in the microenvironment of periodontitis.…”

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confidence: 99%

A20 inhibits osteoclastogenesis via TRAF6‐dependent autophagy in human periodontal ligament cells under hypoxia

et al. 2020

Cell Proliferation

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Objectives A20 exerts an anti‐osteoclastogenic effect through the inhibition of NF‐κB signalling in periodontitis. It also regulates autophagy via ubiquitin modification. This study was aimed at exploring the relationship between A20 and autophagy in anti‐osteoclastogenesis in human periodontal ligament cells (hPDLCs) under hypoxia. Materials and Methods Real‐time PCR and Western blot were used to detect relative mRNA and protein levels. The formation of autophagosomes was measured by TEM. Osteoclastic differentiation was assessed by TRAP staining and hydroxyapatite resorption assay. The interactions between different proteins were observed by co‐IP. Results Cells cultured under 2% O₂ exhibited decreased A20 expression and increased RANKL/OPG (R/O) ratio. There was a negative correlation between A20 and TRAF6, and similar results were found with autophagic flux. A20 delayed the increase in R/O ratio under hypoxia. Autophagy in hPDLCs and osteoclast differentiation and hydroxyapatite resorption areas in mouse bone marrow mononuclear cells (BMMCs) were inhibited by A20. Moreover, inhibition of autophagy using 3‐MA resulted in increased expression of A20 and decreased number and function of osteoclasts. In addition, A20 inhibited polyubiquitination at K63 and enhanced that at K48 in TRAF6 to suppress autophagy under hypoxic conditions. Conclusions A20 inhibits osteoclastogenesis via inhibition of TRAF6‐dependent autophagy in hPDLCs under hypoxia. These findings suggest that A20 may be a key gene target during bone loss in periodontitis via TRAF6‐mediated inhibition of autophagy.

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“…A six-month randomized clinical study comparing two dentifrices, one containing fluoride and zinc and the other containing fluoride alone, revealed that the zinc-based dentifrice provided a meaningful clinical reduction in gingivitis and dental plaque [19]. A study performed by Hong and colleagues demonstrated that A20, an amino-acid protein with zinc finger C-terminal domains, may be a potential element in preventing inflammatory bone loss diseases such as periodontitis due to its anti-inflammatory and anti-osteoclastogenic effects [31]. Conversely, researchers have highlighted an association between zinc deficiency and gingivitis [17].…”

Section: Effects Of Zinc On Dental Caries and Periodontal Tissuesmentioning

confidence: 99%

Zinc Adequacy Is Essential for the Maintenance of Optimal Oral Health

et al. 2020

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Zinc, a metal found in the Earth’s crust, is indispensable for human health. In the human body, around 60% of zinc is present in muscles, 30% in bones, and the remaining 10% in skin, hair, pancreas, kidneys and plasma. An adequate zinc balance is essential for the maintenance of skeletal growth, development and function. It is also necessary for basic cellular functions including enzyme activation, cell signaling and energy metabolism. Inadequate zinc status is associated with a wide variety of systemic disorders including cardiovascular impairment, musculoskeletal dysfunctions and oromaxillary diseases. In this article, we briefly discuss the role of zinc deficiency in the genesis of various oromaxillary diseases, and explain why adequate zinc homeostasis is vital for the maintenance of oral and general health.

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Anti‐inflammatory and anti‐osteoclastogenic effects of zinc finger protein A20 overexpression in human periodontal ligament cells

Cited by 30 publications

References 60 publications

Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

A20 inhibits osteoclastogenesis via TRAF6‐dependent autophagy in human periodontal ligament cells under hypoxia

Zinc Adequacy Is Essential for the Maintenance of Optimal Oral Health

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