Shinji Matsuda

Background/Objectives: The optimal management of periodontal treatment in patients receiving direct oral anticoagulants (DOACs) remains poorly established, and bleeding concerns may lead clinicians to delay or limit treatment. We evaluated the clinical efficacy and safety of nonsurgical periodontal treatment in patients receiving DOAC therapy. Methods: This retrospective study included 67 patients receiving continuous DOAC therapy (edoxaban, apixaban, dabigatran, or rivaroxaban) who underwent nonsurgical periodontal treatment without drug discontinuation. Pocket probing depth, bleeding on probing, the periodontal inflamed surface area (PISA), the periodontal epithelial surface area (PESA), and serum inflammatory cytokine levels were evaluated. A ligature-induced-periodontitis mouse model was also used to assess the effect of apixaban on alveolar bone loss. Results: Nonsurgical periodontal treatment significantly reduced the PISA (42.9%) and PESA (10.8%) in the overall DOAC cohort, with no postoperative bleeding complications. Significant reductions in periodontal parameters were seen in the edoxaban (PISA: 44.2%, PESA: 10.9% reduction), apixaban (PISA: 45.6%, PESA: 11.7% reduction), and dabigatran (PISA: 61.3%, PESA: 16.1% reduction) groups, with no significant changes in the rivaroxaban group. Baseline PISA was positively correlated with baseline serum levels of interleukin-4 (r = 0.33), interleukin-1 beta (r = 0.29), interleukin-6 (r = 0.25), and interleukin-10 (r = 0.30). In the mouse model, apixaban administration did not aggravate ligature-induced alveolar bone loss. Conclusions: Basic periodontal treatment appears to be safe and effective for patients prescribed DOACs and may reduce local periodontal inflammation, resulting in systemic inflammatory burden. These findings support proactive periodontal intervention in patients receiving DOAC therapy, regardless of the specific anticoagulant used.

Background/Objectives: Estrogen is a key female hormone; however, its role in periodontitis remains poorly understood. This study investigated the effects of 17β-estradiol (E2) on experimental periodontitis using an ovariectomy (OVX) model with E2 administration. Methods: Female mice aged 8–10 weeks underwent OVX, followed by induction of ligature-induced periodontitis, and subsequent quantification of alveolar bone resorption. Additional groups received an aromatase inhibitor or E2 supplementation after OVX, with subsequent induction of periodontitis and evaluation of bone resorption. Histological analysis assessed multinucleated giant cells and tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface. Gingival tissue was analyzed for gene expression related to osteoclastogenesis. The effect of E2 on osteoclast differentiation from bone marrow cells was also examined. Results: OVX significantly reduced serum E2 levels and decreased alveolar bone resorption. Aromatase inhibitor administration similarly reduced bone loss. Histological evaluation revealed a reduced number of resorbing osteoclasts in OVX mice, whereas E2 supplementation increased osteoclast numbers. No significant changes in inflammatory cytokine or receptor activator of nuclear factor-kappa B ligand (RANKL) expression were observed. E2 promoted osteoclast differentiation in vitro, and treatment with E2 prior to RANKL stimulation further increased the number of osteoclasts. This effect was suppressed by an estrogen receptor antagonist. Moreover, E2 enhanced the expression of osteoclast differentiation–associated genes in the presence of RANKL, an effect abolished by tamoxifen. Conclusions: E2 increased alveolar bone resorption in experimental periodontitis, likely by promoting osteoclast differentiation, independent of inflammatory cytokine or RANKL gene expression.

This study aimed to evaluate cytokine profiling in a periapical lesion to provide a rationale for future treatment strategies for periapical lesions. Thirteen samples of exudative fluid were collected from such a lesion directly through the root canal. Cytokine profiling was performed using the Bio-Plex system. CXCL10 (C-X-C motif chemokine ligand 10, IP10) was found to be elevated in apical exudates of patients exhibiting favorable healing. To evaluate the role of CXCL10 in cell migration, a Transwell assay was conducted using bone marrow-derived mononuclear cells (BMMCs). Different types of cytokines were detected from the samples of periapical lesion at the initial visit. However, cytokine production varied across patient samples. Release of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and tumor necrosis factor (TNF)-α showed differential expression. Comparison of cytokine profiles indicated that cytokine production was variable before and after root canal treatment. In vitro, CXCL10 significantly improved BMMC migration in a dose-dependent manner, supporting clinical findings that elevated CXCL10 levels are associated with favorable healing in apical lesions. Although this study was limited by the small sample size and exploratory design, the cytokine profile of periapical lesions may be useful for assessing the condition of periapical lesions and modulating the immune response to bacterial infection.

Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients’ neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.

Periodontal inflamed surface area (PISA) and masticatory efficiency have been used to evaluate the relationship between systemic diseases and oral diseases. However, clear standards for PISA values and masticatory efficiency in relation to the severity of periodontitis are lacking. This study aims to evaluate PISA values and masticatory efficiency based on the 2018 periodontal status classification system. In total, 153 healthy participants diagnosed with periodontitis were included in the study. The diagnosis was based on the 2018 periodontal status classification. PISA values and masticatory efficiency were measured at baseline and after initial periodontal therapy. PISA demonstrated a higher area under the curve for Stage III (0.815) and Grade B (0.85). At baseline, PISA was showed significant negative correlation with masticatory efficiency (B coefficient [95% CI]: -0.02 [-0.03, -0.006], p < 0.01). Following periodontal therapy, both PISA values and masticatory efficiency showed significant improvements, with median PISA values changing from 856 at baseline to 277.5 after treatment, and mean masticatory efficiency increasing from 153.3 to 166.9. After initial periodontal therapy, PISA values were significantly higher in patients classified as Stage IV and Grade C compared to those with other stages and grades. Age exhibited a significant negative correlation with changes in PISA (B coefficient [95%CI]: -11.8 [-20.3, -3.19]), and change in PISA value was significantly positively related to the increase in masticatory efficiency (B coefficient [95%CI], 0.02 [(0.0002, 0.03]). In patients with periodontitis, changes in periodontitis classification were associated with increased PISA values and decreased masticatory efficiency. Periodontal therapy improved PISA and masticatory efficiency values. However, the extent of improvement was less pronounced in patients with higher stages and grades of periodontitis. It is essential to consider the interplay between increased PISA and decreased masticatory efficiency when treating patients with severe periodontitis.

This study aimed to elucidate the pathogenesis of idiopathic gingival fibromatosis (IGF). Human gingival fibroblasts (hGFs) were isolated from patients with IGF and periodontitis. Differential gene expression in the hGFs was analyzed using RNA sequencing. Extracellular matrix-related gene expression in the hGFs was analyzed. The effect of specific protein (SP)1 inhibitor or recombinant human transglutaminase 2 (rh-TGM2) on biglycan (BGN) expression in hGFs was also determined. RNA sequencing showed that TGM2 expression was downregulated and BGN mRNA expression was upregulated in patients with IGF relative to periodontitis. rh-TGM2 stimulation of hGFs in patients with IGF significantly reduced BGN expression. SP1 inhibitors downregulated BGN expression in the hGFs. BGN upregulation via SP1 causes TGM2 downregulation in gingival fibroblasts in IGF.

Drug‐induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of n ‐butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study, NR4A1 mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA‐seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that NR4A1 mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of COL1A1 expression, which was upregulated by TGF‐β. BP also ameliorated gingival overgrowth in DIGE mice and reduced Col1a1 and Pai1 expression. BP also decreased Il1β mRNA expression in gingival tissue in DIGE. RNA‐seq results showed an increase in the expression of several genes related to mitogen‐activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP‐induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE.

Objective: This study aimed to investigate the factors influencing the clinical outcomes of regenerative therapy using recombinant human fibroblast growth factor‐2 (rhFGF‐2).Background: rhFGF‐2 promotes periodontal regeneration, and identifying the factors influencing this regeneration is important for optimizing the effectiveness of rhFGF‐2.Methods and Materials: This study used a hospital information‐integrated database to identify patients who underwent periodontal regenerative therapy with rhFGF‐2. Factors included age, smoking status, diabetes mellitus (DM), periodontal inflamed surface area (PISA) at the initial visit, whether the most posterior tooth was involved or not, and preoperative radiological bone defect angle. Periodontal regenerative therapy outcomes were defined as good if radiographic bone fill ≥35% or periodontal pocket closure at 9–15 months after surgery. Bone fill rate (%) and periodontal pocket depth (mm) were also used as outcome measures. Factors were evaluated by simple regression analysis, and then the association between factors and the outcomes was determined by multivariate analysis.Results: PISA and age at the first visit did not significantly influence the success or failure of bone fill rate byrhFGF‐2. However, DM, radiographic bone defect angle, and the most posterior tooth significantly influenced the regenerative effect (success/failure in bone fill) of rhFGF‐2. The most posterior tooth was significantly associated with bone fill rate by rhFGF‐2. Examination of the association between pocket closure and factors shows that the most posterior tooth significantly influenced. The most posterior tooth and preoperative PPD were significantly associated with pocket reduction depth. For the most posterior tooth, a significantly higher bone regeneration rate (p < .05) was observed with a combination of autologous bone graft and rhFGF‐2 than with rhFGF‐2 alone, and the effect was significant in multivariate analysis.Conclusions: The radiographic bone defect angle, the involvement of most posterior teeth, and the presence of DM influenced the effectiveness of rhFGF‐2 in periodontal regeneration. However, PISA values and age at the initial visit had no significant effect.

Objective: The purpose of this study is to investigate regenerative process by immunohistochemical analysis and evaluate periodontal tissue regeneration following a topical application of BDNF to inflamed 3‐wall intra‐bony defects.Background: Brain‐derived neurotrophic factor (BDNF) plays a role in the survival and differentiation of central and peripheral neurons. BDNF can regulate the functions of non‐neural cells, osteoblasts, periodontal ligament cells, endothelial cells, as well as neural cells. Our previous study showed that a topical application of BDNF enhances periodontal tissue regeneration in experimental periodontal defects of dog and that BDNF stimulates the expression of bone (cementum)‐related proteins and proliferation of human periodontal ligament cells.Methods: Six weeks after extraction of mandibular first and third premolars, 3‐wall intra‐bony defects were created in mandibular second and fourth premolars of beagle dogs. Impression material was placed in all of the artificial defects to induce inflammation. Two weeks after the first operation, BDNF (25 and 50 μg/mL) immersed into atelocollagen sponge was applied to the defects. As a control, only atelocollagen sponge immersed in saline was applied. Two and four weeks after the BDNF application, morphometric analysis was performed. Localizations of osteopontin (OPN) and proliferating cell nuclear antigen (PCNA)‐positive cells were evaluated by immunohistochemical analysis.Results: Two weeks after application of BDNF, periodontal tissue was partially regenerated. Immunohistochemical analyses revealed that cells on the denuded root surface were positive with OPN and PCNA. PCNA‐positive cells were also detected in the soft connective tissue of regenerating periodontal tissue. Four weeks after application of BDNF, the periodontal defects were regenerated with cementum, periodontal ligament, and alveolar bone. Along the root surface, abundant OPN‐positive cells were observed. Morphometric analyses revealed that percentage of new cementum length and percentage of new bone area of experimental groups were higher than control group and dose‐dependently increased.Conclusion: These findings suggest that BDNF could induce cementum regeneration in early regenerative phase by stimulating proliferation of periodontal ligament cells and differentiation into periodontal tissue cells, resulting in enhancement of periodontal tissue regeneration in inflamed 3‐wall intra‐bony defects.