マウス破骨細胞形成における抗微生物ペプチド Cathelicidin-related antimicrobial peptide （CRAMP）の役割）

Cathelicidin-related antimicrobial peptide (CRAMP) not only kills bacteria but also binds to lipopolysaccharide (LPS) to neutralize its activity. CRAMP is highly expressed in bone marrow and its expression is reported to be up-regulated by inflammatory and infectious stimuli. Here, we examined the role of CRAMP in murine osteoclastogenesis. Osteoclasts were formed in co-cultures of osteoblasts and bone marrow cells in response to 1a,25-dihydroxyvitamin D3 [1a,25(OH)2D3], prostaglandin E2(PGE2), and Toll-like receptor (TLR) ligands such as LPS and flagellin through the induction of receptor activator of nuclear factor-jB ligand(RANKL) expression in osteoblasts. CRAMP inhibited the osteoclastogenesis in co-cultures treated with LPS and flagellin, but not in those treated with 1a,25(OH)2D3 or PGE2. Although bone marrow macrophages(BMMs) highly expressed formyl peptide receptor 2 (a receptor of CRAMP), CRAMP showed no inhibitory effect on osteoclastogenesis in BMM cultures treated with RANKL. CRAMP suppressed both LPS- and flagellin-induced RANKL expression in osteoblasts and tumour necrosis factor-a (TNF-a) expression in BMMs, suggesting that CRAMP neutralizes the actions of LPS and flagellin. LPS and flagellin enhanced the expression of CRAMP mRNA in osteoblasts. Extracellularly added CRAMP suppressed LPS- and flagellin-induced CRAMP expression. These results suggest that the production of CRAMP promoted by LPS and flagellin is inhibited by CRAMP released by osteoblasts through a feedback regulation. Even though CRAMP itself has no effect on osteoclastogenesis in mice, we propose that CRAMP is an osteoblast-derived protector in bacterial infection-induced osteoclastic bone resorption.2013博士（歯学）松本歯科大

骨芽細胞系列細胞のビタミンD受容体は、in vivo において1α,25(OH)2D3の骨吸収促進活性に必須である

要旨我々は以前、活性型ビタミンD3 [1α,25(OH)2D3]製剤であるエルデカルシトールの薬用量の投与は、骨吸収を抑制することで、骨量を増加させることを報告した。この骨吸収抑制効果は、骨芽細胞系列細胞のビタミンD受容体（VDR）を介することを明らかにした。本研究において我々は、骨芽細胞系列細胞特異的VDR欠損（Ob-VDR-cKO）マウスを用いて、1α,25(OH)2D3の大量投与によって誘導される骨吸収促進が骨芽細胞系列細胞のVDRを介するか否かを調べた。4日間の野生型マウスへの1α,25(OH)2D3（5 µg/kg体重/日）投与は、骨における破骨細胞数を増加させ、骨吸収マーカーであるI型コラーゲンC末端テロペプチド（C-terminal crosslinked telopeptide of type I collagen, CTX-I）の血清濃度を上昇させた。骨吸収促進は、血清カルシウム（Ca）値、線維芽細胞増殖因子23（Fibroblast Growth Factor, FGF-23）値の上昇と、体重の減少を伴っていた。このことは、中毒量の1α,25(OH)2D3は、骨吸収促進と高Ca血症を誘導することを示している。対照的に、野生型マウスへの抗Receptor Activator of NF-κB Ligand（RANKL）中和抗体前投与は、1α,25(OH)2D3が誘導する血清CTX-I, CaおよびFGF23値の上昇を抑制した。また、抗RANKL中和抗体前投与は、1α,25(OH)2D3が誘導する体重減少を抑制した。抗RANKL中和抗体前投与マウスの所見と一致して、1α,25(OH)2D3をOb-VDR-cKOマウスに大量投与しても、破骨細胞数、血清CTX-I値、血清Ca値、血清FGF-23値は、有意に上昇せず、また体重も減少しなかった。以上、本研究において、1α,25(OH)2D3の大量投与による骨吸収促進、血清Ca値上昇および毒性作用は、骨芽細胞系列細胞のVDRを介して発揮されることを明らかにした。2020博士（歯学）松本歯科大

Inhibitory effect of Makomotake components on inflammation

Zizania latifolia (wild rice) is native to Eastern and Southeastern Asia. The fungus Ustilago esculenta penetrates this aquatic perennial grass. Makomotake refers to penetration of the Zizania latifolia shoot by Ustilago esculenta. Recent studies demonstrated that Zizania latifolia extracts exhibit diverse biological activities, such as anti–oxidant effects. The purpose of this study was to investigate the anti–inflammatory effect of Makomotake on endotoxin–induced uveitis (EIU) in mice. After the daily oral administration of Makomotake for 5 days, EIU was induced by the injection of a lipopolysaccharide (LPS) into the footpad of mice. At 24 hours–after injection, the eyes were enucleated and cells infiltrating the anterior chamber and vitreous cavity were counted histologically. Makomotake administration significantly reduced the total number of infiltrating cells. In addition, Makomotake suppressed the production of interleukin (IL)–1 β and tumor necrosis factor (TNF)–α in murine macrophages induced by LPS. Our findings show that Makomotake can be used as an anti–inflammatory agent against EIU, and that it may be useful for the treatment of acute uveitis

Successful conservative treatment of anti–resorptive agent–related osteonecrosis of the jaw in a patient with multiple myeloma:A case report

Summary.Bone resorption inhibitors,such as bisphosphonates and denosumab,are widely used to treat bone lesions caused by disorders of bone metabolism,multiple myeloma,and bone metastases from solid tumors,and the occurrence of antiresorptive agentrelated osteonecrosis of the jaw (ARONJ) is increasing.Currently,surgical treatment is recommended;however,case reports are sparse and there is no established global consensus on treatment.We report the case of a 75–year–old female patient with osteonecrosis of the mandible following bisphosphonate administration for the treatment of multiple myeloma,who was cured by conservative treatment alone.The patient had multiple myeloma and,therefore,had been receiving bisphosphonates for about 24 months prior to her first visit to Matsumoto Dental University Hospital.During periodontal treatment,the patient underwent extraction of the left mandibular wisdom tooth.About 6 months later,bone exposure was observed in the same area,and coexisting osteomyelitis of the jaw was diagnosed.Conservative treatment involving oral hygiene instructions,several doses of antibacterial agents,and frequent rinses was chosen for the bone exposure.About 6 months after the start of such treatment,the decayed bone had disappeared,and after 7 months,the mucosa had completely sealed.Disappearance of the findings of osteomyelitis was assessed by MRI.The infection tended to spread during the clinical course of the disease,but improved with conservative treatment alone,and the exposed area of bone has since epithelialized.We reaffirmed the importance of collaboration and sharing information on the medical history and medications between physicians and dentists while treating patients with primary diseases indicated for bisphosphonates

A case of double inferior vena cava with a literature review and proposal for new classification

Summary We encountered a case of double inferior vena cava (DIVC) in a 76 year old male cadaver during anatomy practice at Matsumoto Dental University in 2015. The left and right internal iliac veins drained into the interiliac vein ran horizontal in front of the cape angle and joined the left and right external iliac veins. Then the inferior vena cava on each side originated.The width of the origin of the inferior vena cava were 13.7 mm and 11.6 mm on the right and left side, respectively. Based on the previous DIVCʼs classifications, we attempted to classify the DIVC and iliac venous system by combining the direction of the internal iliac veins (lateral (l), vertical (s), and medial (m)), the inclination of the interiliac veins (lower left to upper right (L to R), horizontal (H), and lower right to upper left (R to L)),and the width of the right and left IVC (RIVC>LIVC, RIVC=LIVC, and RIVCLIVC, H, l-l. In this case, hemi-azygos vein was not found, and the height of the left kidney was lower than the right one. We therefore investigated the co-existence of the venous system and the height of the kidney to the 53 cases and referred to the embryological relationship between them. The present classification provides basic knowledge for the clinical anatomy and surgery of the pelvic region

Preventive Effects of Chlorogenic Acid on Alveolar Bone Loss in Ligature-Induced Periodontitis in Mice

Chlorogenic acid (CGA) is a polyphenol that is present in coffee beans, many vegetables, and fruits. Since CGA has been reported to exert antioxidant and anti-inflammatory effects, it is expected to protect against periodontitis. In the present study, we used a ligature-induced experimental periodontitis model and investigated the beneficial effects of CGA against alveolar bone resorption caused by experimental periodontitis. To examine the inhibitory effects of CGA on bone loss, a ligature was wrapped around the maxillary right second molar, and CGA was intraperitoneally injected once a day for 2 weeks. In another experiment to investigate the restorative effects of CGA on bone loss, a ligature was wrapped around the maxillary right second molar for 2 weeks, it was then removed, and CGA was intraperitoneally injected once a day for 2 weeks. At the end of the experiments, the maxillae were removed, and CT images were taken. Alveolar bone loss was measured as the distance from the cement–enamel junction to the alveolar crest. The statistical analysis was performed using GraphPad Prism6 (Dunn’s multiple comparison test). The results revealed that the ratio of the buccal alveolar bone loss (vs. the bone loss on the nonligated side) induced by ligation was significantly decreased by the administration of CGA (5 mg/kg) for 2 weeks. Moreover, the bone loss ratio on the buccal and palatal sides after 2 weeks of ligation was significantly decreased by the 2-week administration of CGA (5 mg/kg). The present results revealed that CGA exerted preventive effects against alveolar bone loss caused by experimental periodontitis