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Aims/Introduction The association between diabetes and periodontal disease is considered to be bidirectional. However, there is still controversy surrounding the relationship between periodontal disease and type 1 diabetes. We investigated whether insulin improves periodontitis without any local treatments for periodontitis under type 1 diabetes conditions using the ligature‐induced experimental periodontitis model. Materials and Methods Type 1 diabetic rats were induced by streptozotocin injection. Experimental periodontitis was induced by ligature in normal and diabetic rats. Half of the diabetic rats were treated with insulin. Two weeks after the ligature, periodontitis was evaluated. Results Insulin treatment significantly improved inflammatory cell infiltration and inflammatory cytokine gene expression, leading to suppression of alveolar bone loss, in the periodontitis of diabetic rats. Insulin also suppressed the periodontitis‐increased nitric oxide synthase‐positive cells in periodontal tissue of the diabetic rats. Even without induction of periodontitis, diabetic rats showed decreased gingival blood flow and an increased number of nitric oxide synthase‐positive cells in the gingiva and alveolar bone loss compared with normal rats, all of which were ameliorated by insulin treatment. We further confirmed that insulin directly suppressed lipopolysaccharide‐induced inflammatory cytokine expressions in THP‐1 cells. Conclusions There were abnormalities of periodontal tissue even without the induction of periodontitis in streptozotocin‐induced diabetic rats. Insulin treatment significantly ameliorated periodontitis without local periodontitis treatment in diabetic rats. These data suggest the therapeutic impacts of insulin on periodontitis in type 1 diabetes. There was a slight increase in the numbers of inflammatory cells in the gingiva on the periodontitis side of normal rats and on the control side of diabetic rats. The inflammatory cells were markedly increased on the periodontitis side of diabetic rats. Insulin treatment decreased the inflammatory cells in the periodontitis gingiva of diabetic rats.

Gelatin methacryloyl (GelMA) is a versatile biomaterial that has been used in various biomedical fields. UV light is commonly used to photocrosslink such materials; however, its use has raised several biosafety concerns. We investigated the mechanical and biological properties of a visible-wavelength (VW)-light-crosslinked gelatin-based hydrogel to evaluate its viability as a scaffold for bone regeneration in bone-destructive disease treatment. Irgacure2959 or riboflavin was added as a photoinitiator to create GelMA solutions. GelMA solutions were poured into a mold and exposed to either UV or VW light. KUSA-A1 cell-laden GelMA hydrogels were crosslinked and then cultured. Mechanical characterization revealed that the stiffness range of GelMA–RF hydrogel was suitable for osteoblast differentiation. KUSA-A1 cells encapsulated in GelMA hydrogels photopolymerized with VW light displayed significantly higher cell viability than cells encapsulated in hydrogels photopolymerized with UV light. We also show that the expression of osteogenesis-related genes at a late stage of osteoblast differentiation in osteoblasts encapsulated in GelMA–RF hydrogel was markedly increased under osteoblast differentiation-inducing conditions. The GelMA–RF hydrogel served as an excellent scaffold for the encapsulation of osteoblasts. GelMA–RF hydrogel-encapsulated osteoblasts have the potential not only to help regenerate bone mass but also to treat complex bone defects associated with bone-destructive diseases such as periodontitis.

Periodontal disease, a major cause of tooth loss, is an infectious disease caused by bacteria with the additional aspect of being a noncommunicable disease closely related to lifestyle. Tissue destruction based on chronic inflammation is influenced by host and environmental factors. The treatment of periodontal disease varies according to the condition of each individual patient. Although guidelines provide standardized treatment, optimization is difficult because of the wide range of treatment options and variations in the ideas and skills of the treating practitioner. The new medical concepts of “precision medicine” and “personalized medicine” can provide more predictive treatment than conventional methods by stratifying patients in detail and prescribing treatment methods accordingly. This requires a new diagnostic system that integrates information on individual patient backgrounds (biomarkers, genetics, environment, and lifestyle) with conventional medical examination information. Currently, various biomarkers and other new examination indices are being investigated, and studies on periodontal disease-related genes and the complexity of oral bacteria are underway. This review discusses the possibilities and future challenges of precision periodontics and describes the new generation of laboratory methods and advanced periodontal disease treatment approaches as the basis for this new field.

Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40–75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c ≥ 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25–4.78), and type 2 patients with HbA1c ≥ 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00–1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.

Aims/Introduction The involvement of glucose‐dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose‐dependent insulinotropic polypeptide receptor‐knockout mice (GIPRKO). We also investigated the anti‐inflammatory effect of GIP in a culture system. Materials and Methods Experimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide‐induced gene expressions in THP‐1 cells were evaluated. Results Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor‐α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac‐1‐positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac‐1‐positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide‐induced tumor necrosis factor‐α and nitric oxide synthase gene expression in a dose‐dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide‐induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway. Conclusions These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti‐inflammatory effect on periodontitis in addition to its glucose‐lowering effect. Induction of periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue.

Periodontal disease is considered one of the diabetic complications with high morbidity and severity. Recent studies demonstrated the involvement of the epigenome on diabetic complications. Histone modifications change chromatin architecture and gene activation. Histone modifications have been reported to alter chromatin structure and regulate gene transcription. In this study, we investigated the impacts of H3 lysine 4 trimethylation (H3K4me3) and specific histone methyltransferases of H3K4 methylation, su(var)3-9, enhancer-of-zeste, and trithorax domain 1A (SETD1A) on periodontal tissue affected by the diabetic condition. We observed the increase in H3K4me3 and SETD1A in gingival tissue of diabetic rats compared with the normal rats. Cultured human fibroblasts (hGFs) confirmed a high glucose-induced increase in H3K4me3 and SETD1A. We further demonstrated that high glucose increased the gene expression of matrix metalloproteinase (MMP) 1 and MMP13, which were canceled by sinefungin, an SETD1A inhibitor. Our investigation suggests that diabetes triggers histone modifications in the gingival tissue, resulting in gingival inflammation. Histone modifications may play crucial roles in the development of periodontal disease in diabetes.

Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone loss and may exert an adverse impact on systemic health. Periodontal disease may be associated with hepatocellular carcinoma (HCC); however, the mechanism of such an association is unknown. In this study, Stelic Animal model (STAM) mice, a model of nonalcoholic steatohepatitis (NASH)-HCC, were induced to develop periodontitis and subjected to histopathological and immunological analyses. HCC progression was greater in STAM mice with experimental periodontitis compared with that in STAM mice without experimental periodontitis. Tumor necrosis factor-α (TNFα), matrix metalloproteinase-9 (MMP9), collagen 1, and angiopoietin-like protein 2 (ANGPTL2) gene expression was significantly increased in the liver of the periodontitis group. ANGPTL2 was previously reported to be involved in the pathogenesis of periodontitis, and HCC and ANGPTL2 protein tended to be more abundant in the pocket epithelium of STAM mice with experimental periodontitis than in control STAM mice. ANGPTL2 levels in the serum of STAM mice with experimental periodontitis tended to be higher than in control STAM mice. Our results indicate that ANGPTL2 is produced in chronically inflamed periodontal tissue and then travels to the liver via the bloodstream where it accumulates to promote the progression of hepatocellular carcinoma.

The effect of Mfa1 fimbriae of Porphyromonas gingivalis on the progression of bone resorption remains unclear, especially compared with another fimbriae, FimA. We investigated the effect of Mfa1 on osteoclastogenesis together with FimA. We also investigated the role of Toll-like receptors (TLRs) in Mfa1 recognition during osteoclast differentiation. Receptor activator of nuclear factor κβ ligand (RANKL)-prestimulated RAW264 cells were used to examine the effects of purified Mfa1 fimbriae. The number of osteoclasts was examined by tartrate-resistant acid phosphate (TRAP) staining, osteoclast activation was investigated by bone resorption assays, and gene expression of differentiation markers was examined by quantitative real-time PCR. Transfection of Tlr2 and Tlr4 siRNAs into RAW264 cells was also employed and their role in Mfa1 recognition was investigated. Mfa1 effectively induced the formation of TRAP-positive multinucleated cells and activated osteoclasts. Mfa1 also increased gene expression of Acp5, Mmp9, and Ctsk in RANKL-prestimulated RAW264 cells compared with the control. The osteoclastogenesis induced by Mfa1 was significantly decreased in cells transfected with Tlr2 or Tlr4 siRNAs compared with control siRNA. Our results revealed the role of Mfa1 fimbriae in osteoclastogenesis that may contribute to the partial elucidation of the mechanisms of periodontal disease progression and the development of new therapeutic strategies.

Apical periodontitis, an inflammatory lesion causing bone resorption around the apex of teeth, is treated by eradicating infectious bacteria from the root canal. However, it has a high recurrence rate and often requires retreatment. We investigated the bactericidal effect of antimicrobial photodynamic therapy (aPDT)/photodynamic antimicrobial chemotherapy (PACT) using indocyanine green (ICG)-loaded nanospheres coated with chitosan and a diode laser on a biofilm of Enterococcus faecalis, a pathogen of refractory apical periodontitis. Biofilm of E. faecalis was cultured in a porcine infected root canal model. ICG solution was injected into the root canal, which was then irradiated with a laser (810 nm wavelength) from outside the root canal. The bactericidal effect was evaluated by colony counts and scanning electron microscopy. The result of the colony counts showed a maximum 1.89 log reduction after irradiation at 2.1 W for 5 min. The temperature rise during aPDT/PACT was confirmed to be within a safe range. Furthermore, the light energy transmittance through the root was at a peak approximately 1 min after the start of irradiation, indicating that most of the ICG in the root canal was consumed. This study shows that aPDT/PACT can suppress E. faecalis in infected root canals with high efficiency.

Angiopoietin-like protein 2 (ANGPTL2) maintains tissue homeostasis by inducing inflammation and angiogenesis. It is produced in infiltrating immune cells or resident cells, such as adipocytes, vascular endothelial cells, and tumor cells. We hypothesized that ANGPTL2 might play an important role as a unique mediator in both systemic and periodontal disease. We demonstrated an increased ANGPTL2 concentration in gingival crevicular fluid from chronic periodontitis patients. Porphyromonas gingivalis lipopolysaccharide (LPS) treatment strongly induced ANGPTL2 mRNA and protein levels in Ca9-22 human gingival epithelial cells. Recombinant human ANGPTL2 increased interleukin 1β (IL-1β), IL-8, and tumor necrosis factor-α (TNF-α) mRNA and protein levels in Ca9-22 cells. Small-interfering (si)RNA-mediated ANGPTL2 knockdown in Ca9-22 cells reduced IL-1β, IL-8 and TNF-α mRNA and protein levels compared with control siRNA (p<0.01) in P. gingivalis LPS-stimulated Ca9-22 cells. Antibodies against integrin α5β1, an ANGPTL receptor, blocked induction of these inflammatory cytokines in P. gingivalis LPS-treated Ca9-22 cells, suggesting that secreted ANGPTL induces inflammatory cytokines in gingival epithelial cells via an autocrine loop. The classic sequential cascade of P. gingivalis LPS → inflammatory cytokine induction is well established. However, in the current study, we reveal a novel cascade comprising sequential P. gingivalis LPS → ANGPTL2 → integrin α5β1 → inflammatory cytokine induction, which might be responsible for inducing potent periodontal disorganization activity in gingival epithelial cells. Via this pathway, ANGPTL2 functions in the pathogenesis of periodontitis and contributes to prolonging chronic inflammation in patients with systemic disease.