Periodontal disease is a chronic inflammatory disorder characterized by progressive destruction of periodontal tissues, including alveolar bone resorption, primarily caused by dental biofilm accumulation. The progression of periodontal disease involves factors derived from periodontal pathogenic bacteria, coupled with environmental factors, such as smoking and stress. Additionally, host-dependent factors closely linked to the regulation of immune responses and inflammatory reactions play a critical role. Our research focused on elucidating the homeostatic mechanisms in periodontal tissues. We extensively studied the role of adenosine and the response of periodontal tissues to hypoxia. Through the activation of its receptors, adenosine modulates inflammatory reactions in the gingival fibroblasts and gingival epithelial cells. CD73, an enzyme responsible for extracellular production of adenosine, has been shown to play a role in promoting the differentiation of osteoblasts. Gingival epithelial cells cultured under hypoxic conditions showed suppressed IL-6 and IL-8 production induced by IL-1β in a hypoxia inducible factor-1α (HIF-1α) -dependent manner. We also found that in gingival fibroblasts and periodontal ligament cells, the production of extracellular matrices such as collagen and PLAP-1 was enhanced under hypoxia. The first half of this article provides an overview of our findings.

Although the progression of periodontal disease can be suppressed by mechanical removal of the dental biofilm, this alone cannot regenerate the lost periodontal tissue. Treatment involving guided tissue regeneration membranes or using enamel matrix proteins or fibroblast growth factor 2 can be effective for cases of mild-to-moderate periodontal tissue defects. However, there is no well-established regenerative therapy for severe periodontal tissue destruction. We have been working on the development of a therapy for severe periodontal disease involving autologous transplantation of adipose tissue-derived mesenchymal stem cells. In the second part of this article, we provide an overview of our research achievements, including the results from basic research and a clinical study, and introduce our current endeavors.

Diabetes mellitus is a major risk factor for periodontal disease, considered as one of systemic disease in the field of periodontal medicine. For mimicking the condition of diabetes mellitus, an over-nourished model, i.e., high glucose environment, is often used. Under-nutrition is often a problem in the aging population, but the effect of under-nutrition on hard tissue regeneration is unknown. In this study, we investigated the effects of glucose deprivation on hard tissue differentiation in mouse osteoblasts.

Mouse osteoblast-like cells (MC-3T3-E1) were established from mouse femurs in primary culture and immortalized in α-MEM in the presence of a glucose concentration of 100 mg/dL as a physiological control and 0 mg/dL as a model of glucose deprivation. The effects of glucose deprivation on the MC-3T3-E1 osteoblasts gene expression related to glucose metabolism were screened and compared with the presence of alkaline phosphatase and calcium deposition in the extracellular matrix.

Real-Time PCR Array analysis showed that the expressions of eight genes were decreased by 30% in the glucose-deprived group as compared with the physiological control group at 1 week of culture. The expression of pdk-1 mRNA, a gene involved in osteoblast differentiation and survival, was significantly decreased. BX-912, an inhibitor of PDK-1, decreased the cell proliferative ability and hard tissue differentiation ability in the control group as in the glucose-deprived group.

These results suggest that hard tissue differentiation in MC-3T3-E1 osteoblasts is mediated by PDK-1, which is involved in glucose metabolism.

Orthodontic treatment in patients with generalized aggressive periodontitis (GAP) is occasionally associated with rapid attachment loss, bone resorption, and gingival recession. This case described periodontal therapy included periodontal regenerative surgery for GAP patient which repeated acute symptoms due to inappropriate orthodontic therapy. Periodontal treatment, including regenerative periodontal surgery was successfully performed and the condition of the good periodontal tissue remained stable. Therefore, orthodontic treatment should be performed in GAP patients only after elimination of putative bacterial pathogens.

Cemental tears (CTs) often resemble the clinical status of periodontitis. Some CTs are subclinical, which cannot be identified at the diagnostic stage and are first identified during periodontal surgical treatment. In this case series, we describe the treatment and prognosis of four cases of "subclinical CTs" treated by periodontal tissue regenerative therapy.

Cases: The 4 patients (women aged 55,70,71 and 77 years old) visited our dental school and were diagnosed as having chronic periodontitis. Possible risk factors such as bruxism, age and smoking were identified by interviewing the patients. The clinical findings before and after treatment were recorded. Results: During periodontal surgery, CTs were found, and regenerative periodontal therapy was performed with Emdogain^®, REGROTH^® or GTR membrane, after confirming root debridement. Significant improvement of all the clinical indices was recorded after treatment, and the improvement was sustained for at least 5 years in all cases.

Conclusion: These clinical cases suggest that CTs may cause rapid destruction of periodontal tissues and that periodontal regenerative therapy could be an effective treatment modality for CTs.