Nobuyoshi Tomomatsu

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

TNF‐α is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF‐α. Several lines of evidence show inhibition of osteoblastogenesis by TNF‐α in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF‐α. However, little is known about the inhibitory role of TNF‐α in bone formation/osteogenesis in vivo. The purpose of this study was to investigate the role of TNF‐α in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF‐α–deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF‐α levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF‐α signaling pathway by preventing transmission of the NF‐κB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF‐α might play a major role in LPS‐induced inhibition of osteogenesis under inflammatory conditions.

Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss

We report here a nanogel-mediated peptide drug delivery system. Low stability is a major drawback towards clinical application of peptide drugs. The W9-peptide, a TNF-alpha and RANKL antagonist, was used as a model for testing the feasibility of cholesterol-bearing pullulan (CHP)-nanogel as the drug delivery system. We found CHP-nanogel could form complex with the W9-peptide and prevents its aggregation in vitro. Murine bone resorption model using low dietary calcium was used to investigate the in vivo effect. Two-time-injection of 24 mg/kg W9-peptide per day with or without CHP-nanogel was given for 7 days. Thereafter, radiological, and histological assessments were performed. The injections of the W9-peptide (24 mg/kg) with CHP-nanogel prevented the reduction in bone mineral density whereas the same dose without CHP-nanogel could not show any inhibitory effect. Histomorphometric analysis of tibiae showed significant decrease of osteoclast number and surface in CHP-W9 complex treated group and the levels of urinary deoxypyridinoline reflected these decrease of bone resorption parameters. Taken together these data shows that CHP-nanogel worked as a suitable carrier for the W9-peptide and it prevented aggregation and increased the stability of the W9-peptide. This study reveals the feasibility of CHP-nanogel-mediated peptide delivery in preventing bone resorption in vivo.

Primary ameloblastic carcinoma of the maxilla: A case report and literature review

Ameloblastic carcinoma (AC) is a rare malignant odontogenic neoplasm that tends to occur in the mandible rather than in the maxilla. This malignancy is classified as a tumor that combines the morphological features of ameloblastoma and carcinoma, regardless of the presence or absence of metastasis. In addition, AC has been classified into two types, primary and secondary. The former develops de novo and the latter develops by malignant transformation of a pre-existing benign ameloblastoma. The present study describes the case of a 22-year-old patient with primary AC of the maxilla. A review of the literature focusing on the clinical details, treatment results and histopathological and phenotypic information available for ameloblastic carcinoma of the maxilla from a 60-year period was also performed. As a result, it was found that primary AC is dominant in the maxilla and does not exhibit an aggressive phenotype compared with secondary AC. In addition, the presence of recurrence was found to correlate with mortality, indicating that early, aggressive and complete removal of the tumor is the best treatment for survival.

A structural modulator of tumor necrosis factor type 1 receptor promotes bone formation under lipopolysaccharide-induced inflammation in a murine tooth extraction model

Recently an increase in the serum levels of a bone formation marker after anti-tumor necrosis factor (TNF)-α therapy in rheumatoid arthritis patients has been reported. However, there remains no direct evidence that TNF-α antagonist could accelerate bone formation under inflammatory condition. Cavity-induced allosteric modification (CIAM) compound, F002, is a newly developed-TNF-α antagonist, which was designed by using the structure of TNF type 1 receptor, thus preventing TNF-α-induced signaling. In this study, we examined whether the CIAM compound can promote bone formation under inflammatory condition induced by lipopolysaccharide (LPS). Thirty-six 10-week-old male mice (C57BL/6J) were used. Half of the mice received 10 mg/kg LPS, while the other half received PBS. Thereafter, incisor extraction was performed at 4 days after either LPS or PBS injection. Intraperitoneal injections of 2 mg/kg/day, 4 mg/kg/day CIAM, or vehicle (10% DMSO) were performed once a day from day 0 to day 7 after incisor tooth extraction. The mice were sacrificed at 21 days after the extraction. The regenerated bone mineral density (BMD) in the tooth socket, and the mineral apposition rate and the bone formation rate, direct evidences of bone formation, were significantly decreased in the LPS-injected group compared to the PBS-injected group. CIAM compound dose-dependently prevented the decrease of BMD under the LPS-injected condition, and promoted both the mineral apposition rate and the bone formation rate significantly compared to the LPS-injected group. We did not observe any significant differences among the PBS-injected groups. Taken together, TNF-α antagonist CIAM compound, was found to accelerate bone formation under LPS-induced inflammatory condition.

Aperture width of the osteomeatal complex as a predictor of successful treatment of odontogenic maxillary sinusitis

Odontogenic maxillary sinusitis (OMS) is an inflammatory disease caused by the spread of dental inflammation into the sinus. The long-term administration of antibiotic medicine and/or treatment of the causative tooth are the usual initial treatments. These initial treatments are not always effective, and the reason is not well understood. The purpose of this study was to identify factors of significance that may contribute to the results of the initial treatment of OMS. Thirty-nine patients were studied, divided into two groups according to the results of initial treatment: effective or non-effective. The effective group comprised 20 patients who were cured by initial treatment. The non-effective group comprised 19 patients who required an additional operation. The duration of symptoms, spread into the other sinuses, aperture width of the osteomeatal complex (OMC) on the side of the maxillary sinus, and anatomical variations in the sinuses were compared between the groups. The only significant difference found was in the aperture width of the OMC, which was significantly narrower in the non-effective group than in the effective group. The aperture width of the OMC may be a significant predictor of the effectiveness of initial treatment of OMS.