Genome-wide association studies on periodontitis: A systematic review.

OBJECTIVES: This study aims to systematically review the existing literature and critically appraise the evidence of genome-wide association studies (GWAS) on periodontitis. This study also aims to synthesise the findings of genetic risk variants of periodontitis from included GWAS. METHODS: A systematic search was conducted on PubMed, GWAS Catalog, MEDLINE, GLOBAL HEALTH and EMBASE via Ovid for GWAS on periodontitis. Only studies exploring single-nucleotide polymorphisms(SNPs) associated with periodontitis were eligible for inclusion. The quality of the GWAS was assessed using the Q-genie tool. Information such as study population, ethnicity, genomic data source, phenotypic characteristics(definition of periodontitis), and GWAS methods(quality control, analysis stages) were extracted. SNPs that reached conventional or suggestive GWAS significance level(5e-8 or 5e-06) were extracted and synthesized. RESULTS: A total of 15 good-quality GWAS on periodontitis were included (Q-genie scores ranged from 38-50). There were huge heterogeneities among studies. There were 11 identified risk SNPs (rs242016, rs242014, rs10491972, rs242002, rs2978951, rs2738058, rs4284742, rs729876, rs149133391, rs1537415, rs12461706) at conventional GWAS significant level (p<5x10-8), and 41 at suggestive level (p<5x10-6), but no common SNPs were found between studies. Three SNPs (rs4284742 [G], rs11084095 [A], rs12461706 [T]) from three large studies were from the same gene region-SIGLEC5. CONCLUSION: GWAS of periodontitis showed high heterogeneity of methodology used and provided limited SNPs statistics, making identifying reliable risk SNPs challenging. A clear guidance in dental research with requirement of expectation to make GWAS statistics available to other investigators are needed.

Discovering common pathogenetic processes between periodontitis and Alzheimer's disease by bioinformatics and system biology approach.

BACKGROUND: There is increasing evidence that inflammation plays a key role in the pathophysiology of periodontitis (PT) and Alzheimer's disease (AD), but the roles of inflammation in linking PT and AD are not clear. Our aim is to analyze the potential molecular mechanisms between these two diseases using bioinformatics and systems biology approaches. METHODS: To elucidate the link between PT and AD, we selected shared genes (SGs) with gene-disease-association scores of ≥ 0.1 from the Disease Gene Network (DisGeNET) database, followed by extracting the hub genes. Based on these genes, we constructed gene ontology (GO) enrichment analysis, pathway enrichment analysis, protein-protein interaction (PPI) networks, transcription factors (TFs)-gene networks, microRNAs (miRNAs)-gene regulatory networks, and gene-disease association analyses. Finally, the Drug Signatures database (DSigDB) was utilized to predict candidate molecular drugs related to hub genes. RESULTS: A total of 21 common SGs between PT and AD were obtained. Cell cytokine activity, inflammatory response, and extracellular membrane were the most important enriched items in GO analysis. Interleukin-10 Signaling, LTF Danger Signal Response Pathway, and RAGE Pathway were identified as important shared pathways. IL6, IL10, IL1B, TNF, IFNG, CXCL8, CCL2, MMP9, TLR4 were identified as hub genes. Both shared pathways and hub genes are closely related to endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Importantly, glutathione, simvastatin, and dexamethasone were identified as important candidate drugs for the treatment of PT and AD. CONCLUSIONS: There is a close link between PT and AD pathogenesis, which may involve in the inflammation, ER and mitochondrial function.

PHD2 shRNA-Modified Bone Marrow Mesenchymal Stem Cells Facilitate Periodontal Bone Repair in Response to Inflammatory Condition.

OBJECTIVE: To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modulate periodontal bone repair through the hydroxylase domain-containing protein 2 (PHD2)/hypoxia- inducible factor-1 (HIF-1) signalling pathway in response to inflammatory conditions. METHODS: Osteogenic differentiation of PHD2 shRNA-modified BMMSCs and the possible mechanism were explored in an inflammatory microenvironment stimulated by porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in vitro. The effect of PHD2 gene-modified BMMSCs on periodontal bone loss was evaluated with experimental periodontitis. RESULTS: Pg-LPS stimulation greatly impaired the osteogenic differentiation of BMMSCs, whereas the silence of PHD2 significantly enhanced the osteogenesis of BMMSCs. More importantly, increased level of vascular endothelial growth factor (VEGF) was detected under Pg-LPS stimulation, which was verified to be associated with the augmented osteogenesis. In experimental periodontitis, PHD2-modified BMMSCs transplantation elevated osteogenic parameters and the expression of VEGF in periodontal tissue. CONCLUSION: This study highlighted that PHD2 gene silencing could be a feasible approach to combat inflammatory bone loss by rescuing the dysfunction of seed cells.

Identification of microRNAs expressed in an animal model of periodontal disease and their impact on pathological processes.

MicroRNAs represent a class of small RNAs that act to silence genes post-transcriptionally by inhibiting the translation of target messenger RNAs, and this study aimed to understand how miRNAs influence the set-up of periodontal disease. Periodontitis was induced by inserting a ligature into the left first mandibular molar in a rat model, which was kept for the entire 56 days-time of experiment. After 56 days post-periodontitis induction, the histopathological analysis showed an apical extension of the junctional epithelium, with areas of hyperplasia, exocytosis, and a mixed inflammatory infiltrate with a predominance of neutrophils, lymphocytes, and eventual plasma cells in the deeper layers. The cement surface showed areas of irregularity, covered by cementoblasts and irregular surfaces, confirming the set-up of periodontitis. In the sequencing analysis, 26,404 genes were identified, with 132 reaching statistical significance. Among genes with a statistical difference, 18 were found to encode for microRNAs. The identified microRNAs are primarily involved in bone remodeling by acting on fibroblast growth factors, and collagen production. These outcomes demonstrate a signaling role in bone resorption, which is consistent with the histopathological observations that show the installation of inflammation with epithelial migration and the beginning of the repair process, with cementum resorption. The disclosure of how miRNAs may influence the maintaining of periodontal disease will help the development of new dental materials for the prophylaxis and treatment of alveolar bone resorption.

Exploration of the shared diagnostic genes and mechanisms between periodontitis and primary Sjögren's syndrome by integrated comprehensive bioinformatics analysis and machine learning.

BACKGROUND: Accumulating evidence has showed a bidirectional link between periodontitis (PD) and primary Sjögren's syndrome (pSS), but the mechanisms of their occurrence remain unclear. Hence, this study aimed to investigate the shared diagnostic genes and potential mechanisms between PD and pSS using bioinformatics methods. METHODS: Gene expression data for PD and pSS were acquired from the Gene Expression Omnibus (GEO) database. Differential expression genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) were utilized to search common genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore biological functions. Three machine learning algorithms (least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF)) were used to further identify shared diagnostic genes, and these genes were assessed via receiver operating characteristic (ROC) curves in discovery and validation datasets. CIBERSORT was employed for immune cell infiltration analysis. Transcription factors (TFs)-genes and miRNAs-genes regulatory networks were conducted by NetworkAnalyst. Finally, relevant drug targets were predicted by DSigDB. RESULTS: Based on DEGs, 173 overlapping genes were obtained and primarily enriched in immune- and inflammation-related pathways. WGCNA revealed 34 common disease-related genes, which were enriched in similar biological pathways. Intersecting the DEGs with WGCNA results yielded 22 candidate genes. Moreover, three machine learning algorithms identified three shared genes (CSF2RB, CXCR4, and LYN) between PD and pSS, and these genes demonstrated good diagnostic performance (AUC>0.85) in both discovery and validation datasets. The immune cell infiltration analysis showed significant dysregulation in several immune cell populations. Regulatory network analysis highlighted that WRNIP1 and has-mir-155-5p might be pivotal co-regulators of the three shared gene expressions. Finally, the top 10 potential gene-targeted drugs were screened. CONCLUSION: CSF2RB, CXCR4, and LYN may serve as potential biomarkers for the concurrent diagnosis of PD and pSS. Additionally, we identified common molecular mechanisms, TFs, miRNAs, and candidate drugs between PD and pSS, which may provide novel insights and targets for future research on the pathogenesis, diagnosis, and therapy of both diseases.

Maternal Salivary miR-423-5p Is Linked to Neonatal Outcomes and Periodontal Status in Cardiovascular-High-Risk Pregnancies.

Periodontal disease (PD) during pregnancy may trigger systemic inflammation, increasing the risk of developing cardiometabolic disease (CMD). As a consequence, PD may result in the activation of cellular and molecular pathways, affecting the disease course and pregnancy outcome. Although microRNAs (miRNAs) are considered ideal biomarkers for many diseases, few studies have investigated salivary miRNAs and their role in pregnancy or neonatal outcomes. In this study, we sought to investigate the associations between salivary miRNAs of pregnant women with oral diseases and their effects on neonatal outcomes. Eleven (n = 11) salivary miRNAs from a cohort of pregnant women with oral diseases (n = 32; oral health, H; gingivitis, G; and periodontitis, P) were detected using a previous profiling analysis with an FDR < 0.20 and a fold change (FC) < 0.5 or FC > 2 for the most highly expressed miRNAs. Spearman correlations were performed for 11 salivary microRNAs associated with oral-derived inflammation, which could affect neonatal outcomes during pregnancies at risk for cardiometabolic disease (CMD), defined by the presence of a high pregestational BMI. In addition, ROC curves demonstrated the diagnostic accuracy of the markers used. Upregulation of miR-423-5p expression and a decrease in miR-27b-3p expression were detected in the P-group (p < 0.05), and ROC analysis revealed the diagnostic accuracy of miR-423-5p for discriminating oral diseases, such as gingivitis versus periodontitis (P vs. G, AUC = 0.78, p < 0.05), and for discriminating it from the healthy oral cavity (P vs. H, AUC = 0.9, p < 0.01). In addition, miR-27b-3p and miR-622 were also able to discriminate the healthy group from the P-group (AUC = 0.8, p < 0.05; AUC = 0.8, p < 0.05). miR-483-5p was able to discriminate between the G-group (AUC = 0.9, p < 0.01) and the P-group (AUC = 0.8, p < 0.05). These data support the role of salivary miRNAs as early biomarkers for neonatal outcomes in pregnant women with periodontal disease at high risk for CMD and suggest that there is cross-talk between salivary miRNAs and subclinical systemic inflammation.

Targeted Reprogramming of Pathogenic Fibroblast Genes at the 3'-Untranslated Regions by DNA Nanorobots for Periodontitis.

Periodontitis, with its persistent nature, causes significant distress for most sufferers. Current treatments, such as mechanical cleaning and surgery, often fail to fully address the underlying overactivation of fibroblasts that drives this degradation. Targeting the post-transcriptional regulation of fibroblasts, particularly at the 3'-untranslated regions (3'UTR) of pathogenic genes, offers a therapeutic strategy for periodontitis. Herein, we developed a DNA nanorobot for this purpose. This system uses a dynamic DNA nanoframework to incorporate therapeutic microRNAs through molecular recognition and covalent bonds, facilitated by DNA monomers modified with disulfide bonds. The assembled-DNA nanoframework is encapsulated in a cell membrane embedded with a fibroblast-targeting peptide. By analyzing the 3'UTR regions of pathogenic fibroblast genes FOSB and JUND, we identified the therapeutic microRNA as miR-1-3p and integrated it into this system. As expected, the DNA nanorobot delivered the internal components to fibroblasts by the targeting peptide and outer membrane that responsively releases miR-1-3p under intracellular glutathione. It resulted in a precise reduction of mRNA and suppression of protein function in pathogenic genes, effectively reprogramming fibroblast behavior. Our results confirm that this approach not only mitigates the inflammation but also promotes tissue regeneration in periodontal models, offering a promising therapeutic avenue for periodontitis.

Biological aging mediates the association between periodontitis and cardiovascular disease: results from a national population study and Mendelian randomization analysis.

BACKGROUND: The relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging. METHODS: We included 3269 participants from the National Health and Nutrition Examination Survey (2009-2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera-Doubal method's calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging. RESULTS: Periodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging. CONCLUSIONS: Periodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk.

The promise and challenges of genomics-informed periodontal disease diagnoses.

Recent advances in human genomics and the advent of molecular medicine have catapulted our ability to characterize human and health and disease. Scientists and healthcare practitioners can now leverage information on genetic variation and gene expression at the tissue or even individual cell level, and an enormous potential exists to refine diagnostic categories, assess risk in unaffected individuals, and optimize disease management among those affected. This review investigates the progress made in the domains of molecular medicine and genomics as they relate to periodontology. The review summarizes the current evidence of association between genomics and periodontal diseases, including the current state of knowledge that approximately a third of the population variance of periodontitis may be attributable to genetic variation and the management of several monogenic forms of the disease can be augmented by knowledge of the underlying genetic cause. Finally, the paper discusses the potential utility of polygenic risk scores and genetic testing for periodontitis diagnosis now and in the future, in light of applications that currently exist in other areas of medicine and healthcare.

A novel missense variant in CAT gene causing acatalasemia with gangrenous periodontitis (Takahara's disease).

OBJECTIVES: Acatalasemia is a very rare disorder characterized by gangrenous oral ulcerations and is caused by biallelic variants in the CAT gene which encodes the catalase enzyme that decomposes the hydrogen peroxide molecules to remove their toxic effect. We report two siblings from a consanguineous Egyptian family presenting with joint hyperlaxity, loose dentitions with gangrenous periodontitis, and early loss of teeth. STUDY DESIGN: The patients were clinically suspected to have the periodontal type of Ehlers-Danlos syndrome and thus genetic testing of C1S and C1R causative genes was carried out first by Sanger sequencing then exome sequencing (ES) was considered. RESULTS: No pathogenic variants were detected in C1S and C1R genes then ES revealed a new homozygous missense variant in the CAT gene segregating in the family, c .635 T > G (p.Met212Arg). CONCLUSION: We describe the first Egyptian cases with acatalasemia and expand the mutational spectrum of this rare disorder. Premature loss of teeth is an emerging finding in our cases and addresses the hazardous systemic manifestations associated with the disorder. The rarity of inherited orodental diseases renders the accurate diagnosis difficult and complicates the symptoms. Therefore, the use of advanced molecular technologies is highly advisable for early diagnosis and management of patients.

Causal Relationship between Mitochondrial Biological Function and Periodontitis: Evidence from a Mendelian Randomization Study.

A growing number of studies indicate that mitochondrial dysfunction serves as a pathological mechanism for periodontitis. Therefore, this two-sample Mendelian randomization (MR) study was carried out to explore the causal associations between mitochondrial biological function and periodontitis, because the specific nature of this causal relationship remains inconclusive in existing MR studies. Inverse variance weighting, Mendelian randomization-Egger, weighted mode, simple mode, and weighted median analyses were performed to assess the causal relationships between the exposure factors and periodontitis. The results of the present study revealed a causal association between periodontitis and medium-chain specific acyl-CoA dehydrogenase (MCAD), malonyl-CoA decarboxylase (MLYCD), glutaredoxin 2 (Grx2), oligoribonuclease (ORN), and pyruvate carboxylase (PC). Notably, MCAD and MLYCD are causally linked to periodontitis, and serve as protective factors. However, Grx2, ORN, and PC function as risk factors for periodontitis. Our study established a causal relationship between mitochondrial biological function and periodontitis, and such insights may provide a promising approach for treating periodontitis via mitochondrial regulation.

Correlation of disulfidptosis and periodontitis: New insights and clinical significance.

OBJECTIVES: This study aims to investigate and predict the therapeutic agents associated with disulfidptosis in periodontitis. DESIGN: The dataset GSE10334 was downloaded from the Gene Expression Omnibus (GEO) database and used to train a least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) algorithm to identify genes associated with disulfidptosis in periodontitis. GSE16134 validation sets, polymerase chain reaction (PCR), and gingival immunofluorescence were used to verify the results.Single-gene Gene Set Enrichment Analysis (GSEA) was performed to explore the potential mechanisms and functions of the characterized genes. Immune infiltration and correlation analyses were performed, and competing endogenous RNA (ceRNA) networks were constructed. Effective therapeutic drugs were then predicted using the DGIdb database, and molecular docking was used to validate binding affinity. RESULTS: Six genes (SLC7A11, SLC3A2, RPN1, NCKAP1, LRPPRC, and NDUFS1) associated with disulfidptosis in periodontitis were obtained. Validation results from external datasets and experiments were consistent with the screening results. Single-gene GSEA analysis was mainly enriched for antigen presentation and immune-related pathways and functions.Immune infiltration and correlation analyses revealed significant regulatory relationships between these genes and plasma cells, resting dendritic cell, and activated NK cells. The ceRNA network was visualized. And ME-344, NV-128, and RILUZOLE, which have good affinity to target genes, were identified as promising agents for the treatment of periodontitis. CONCLUSIONS: SLC7A11, SLC3A2, RPN1, NCKAP1, LRPPRC, and NDUFS1 are targets associated with disulfidptosis in periodontitis, and ME-344, NV-128, and RILUZOLE are promising agents for the treatment of periodontitis.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

Prediction of Interactomic HUB Genes in Periodontitis With Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) risk correlates with C-reactive protein (CRP) levels, suggesting systemic inflammation is present well before AMI. Studying different types of periodontal disease (PD), extremely common in individuals at risk for AMI, has been one important research topic. According to recent research, AMI and PD interact via the systemic production of certain proinflammatory and anti-inflammatory cytokines, small signal molecules, and enzymes that control the onset and development of both disorders' chronic inflammatory reactions. This study uses machine learning to identify the interactome hub biomarker genes in acute myocardial infarction and periodontitis. METHODS: GSE208194 and GSE222883 were chosen for our research after a thorough search using keywords related to the study's goal from the gene expression omnibus (GEO) datasets. DEGs were identified from the GEOR tool, and the hub gene was identified using Cytoscape-cytohubba. Using expression values, Random Forest, Adaptive Boosting, and Naive Bayes, widgets-generated transcriptomics data, were labelled, and divided into 80/20 training and testing data with cross-validation. ROC curve, confusion matrix, and AUC were determined. In addition, Functional Enrichment Analysis of Differentially Expressed Gene analysis was performed. RESULTS: Random Forest, AdaBoost, and Naive Bayes models with 99%, 100%, and 75% AUC, respectively. Compared to RF, AdaBoost, and NB classification models, AdaBoost had the highest AUC. Categorization algorithms may be better predictors than important biomarkers. CONCLUSIONS: Machine learning model predicts hub and non-hub genes from genomic datasets with periodontitis and acute myocardial infarction.

Streptococcus gordonii Supragingival Bacterium Oral Infection-Induced Periodontitis and Robust miRNA Expression Kinetics.

Streptococcus gordonii (S. gordonii, Sg) is one of the early colonizing, supragingival commensal bacterium normally associated with oral health in human dental plaque. MicroRNAs (miRNAs) play an important role in the inflammation-mediated pathways and are involved in periodontal disease (PD) pathogenesis. PD is a polymicrobial dysbiotic immune-inflammatory disease initiated by microbes in the gingival sulcus/pockets. The objective of this study is to determine the global miRNA expression kinetics in S. gordonii DL1-infected C57BL/6J mice. All mice were randomly divided into four groups (n = 10 mice/group; 5 males and 5 females). Bacterial infection was performed in mice at 8 weeks and 16 weeks, mice were euthanized, and tissues harvested for analysis. We analyzed differentially expressed (DE) miRNAs in the mandibles of S. gordonii-infected mice. Gingival colonization/infection by S. gordonii and alveolar bone resorption (ABR) was confirmed. All the S. gordonii-infected mice at two specific time points showed bacterial colonization (100%) in the gingival surface, and a significant increase in mandible and maxilla ABR (p < 0.0001). miRNA profiling revealed 191 upregulated miRNAs (miR-375, miR-34b-5p) and 22 downregulated miRNAs (miR-133, miR-1224) in the mandibles of S. gordonii-infected mice at the 8-week mark. Conversely, at 16 weeks post-infection, 10 miRNAs (miR-1902, miR-203) were upregulated and 32 miRNAs (miR-1937c, miR-720) were downregulated. Two miRNAs, miR-210 and miR-423-5p, were commonly upregulated, and miR-2135 and miR-145 were commonly downregulated in both 8- and 16-week-infected mice mandibles. Furthermore, we employed five machine learning (ML) algorithms to assess how the number of miRNA copies correlates with S. gordonii infections in mice. In the ML analyses, miR-22 and miR-30c (8-week), miR-720 and miR-339-5p (16-week), and miR-720, miR-22, and miR-339-5p (combined 8- and 16-week) emerged as the most influential miRNAs.

Toll-like receptor 4 deficiency affects the balance of osteoclastogenesis and osteoblastogenesis in periodontitis.

Toll-like receptor 4 (TLR4) acts as a double-edged sword in the occurrence and development of periodontitis. While the activation of TLR4 in macrophages aids in clearing local pathogens, it can also disrupt innate immune responses, upsetting microecological balance and accelerating the destruction of periodontal bone tissues. To date, the effects of TLR4 on osteogenesis and osteoclastogenesis in periodontitis have not been comprehensively studied. In this study, we investigated the development of periodontitis in the Tlr4-/- mice by ligating their second molars with silk threads. Compared to wild-type (WT) mice, Tlr4-/- mice demonstrated increased resistance to periodontitis-associated bone destruction, as evidenced by decreased bone resorption and enhanced bone regeneration. Mechanistically, the deletion of Tlr4 not only inhibited osteoclast formation by reducing the expression of NFATc1, CTSK and TRAP, but also enhanced osteogenic abilities through increased expression of OCN, OPN and RUNX2. In conclusion, TLR4 tips the balance of osteoclastogenesis and osteogenesis, thereby promoting periodontal bone destruction in periodontitis.

Depression, stress-related disorders and risk for dental caries and periodontitis: A bidirectional and multivariable Mendelian randomization study.

AIMS: Our Mendelian randomization (MR) analysis focused on investigating the bidirectional relationships between major depressive disorder (MDD), anxiety and stress-related disorder (ASRD), and dental caries as well as periodontitis. MATERIALS AND METHODS: We used summary statistics from two studies: an MDD genome-wide association study (GWAS) including 135,458 cases with 344,901 controls and a Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) GWAS based on 12,655 ASRD individuals and 19,225 controls from Denmark. GWASs on dental caries and periodontitis were based on the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. We employed different MR approaches, such as inverse-variance weighted (IVW), MR-Egger, weighted median, and MR-PRESSO, to calculate causal effects. RESULTS: Single-variable MR analysis revealed that ASRD was potentially significantly associated with decayed, missing, and filled tooth surfaces (DMFS) (ß = 0.056; 95 % CI: 0.009, 0.103; p = 0.018). Periodontitis was suggested to be causally related to increased ASRD risk (OR = 1.143, 95 % CI: 1.008, 1.298; p = 0.038). According to the multivariable MR analysis, no significant associations were detected between MDD and ASRD with dental caries and periodontitis, and vice versa. CONCLUSIONS: ASRD demonstrated a potential association with DMFS, and periodontitis was found to potentially impact ASRD according to single-variable MR analysis. Nevertheless, no significant associations were identified between MDD, ASRD, dental caries, or periodontitis after adjusting for smoking status and education level. Hence, more robust genetic instruments are required to validate and reinforce our findings.

Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

The association between polyunsaturated fatty acids and periodontitis: NHANES 2011-2014 and Mendelian randomisation analysis.

BACKGROUND: We aimed to explore the association and potential causality between polyunsaturated fatty acids concentrations and the risk of periodontal disease. MATERIALS AND METHODS: Data were collected from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were used to analyse the associations of the concentrations of omega-3 and omega-6 fatty acids and the omega-6/omega-3 fatty acids ratio with the risk of periodontitis. E-value and propensity score matching (PSM) analyses were used for sensitivity analyses. In addition, two-sample Mendelian randomisation (MR) analyses were performed to assess the potential causal impact of the concentrations of those fatty acids on periodontitis risk. RESULTS: A total of 2462 participants from the NHANES were included. Logistic regression analysis revealed that high omega-3 fatty acids levels were negatively associated with the risk of developing periodontitis (P < 0.05), while the omega-6/omega-3 fatty acids ratio was positively associated with the risk of developing periodontitis (P < 0.05). There was no significant association between omega-6 concentrations and the risk of periodontitis. The findings mentioned above were confirmed by analysis following a 1:1 PSM. Furthermore, MR examination of the two samples indicated no possible causal link between the risk of periodontitis and the concentrations of omega-3 or omega-6 fatty acids or the ratio of omega-6 to omega-3 fatty acids (P > 0.05). CONCLUSION: Although omega-3 fatty acids and the omega-6/omega-3 fatty acids ratio were associated with the risk of periodontitis in cross-sectional studies, the MR results did not support a causal relationship between them. Therefore, there is no indication that an increase in the omega-3 fatty acids concentration or a decrease in the omega-6/omega-3 fatty acids ratio may be beneficial for preventing periodontitis.

lncRNA CDKN2B-AS1 regulates collagen expression.

The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7 × 10- 5 (AUC > 0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 × 10- 25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1 × 10- 5 (AUC = 0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change = 48.5, P < 9 × 10- 24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P = 5.8 × 10- 6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P = 0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.