International Research Center for Molecular Science in Tooth and Bone Diseases

Bunkyō-ku, Japan

International Research Center for Molecular Science in Tooth and Bone Diseases

Bunkyō-ku, Japan
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Sato K.,Tokyo Medical and Dental University | Sato K.,International Research Center for Molecular Science in Tooth and Bone Diseases | Lee J.-W.,Tokyo Medical and Dental University | Sakamoto K.,Tokyo Medical and Dental University | And 9 more authors.
American Journal of Pathology | Year: 2013

The molecular mechanisms underlying bone destruction by invading oral cancer are not well understood. Using IHC, we demonstrated that receptor activator of nuclear factor-κB ligand (RANKL)-positive fibroblasts and cancer cells were located at sites of bone invasion in human oral cancers. HSC3 and HO-1-N-1, human oral cancer cell lines, expressed RANKL and stimulated Rankl expression in the UAMS-32 murine osteoblastic cell line. We discriminated the roles of RANKL synthesized by stromal cells and cancer cells in cancer-associated bone resorption by using species-specific RANKL antibodies against murine RANKL and human RANKL, respectively. Osteoclastogenesis induced by the conditioned medium of HSC3 and HO-1-N-1 cells in a co-culture of murine bone marrow cells and UAMS-32 cells was inhibited by the addition of antibodies against either mouse or human RANKL. HSC3-induced bone destruction was greatly inhibited by the administration of anti-mouse RANKL antibody in a xenograft model. HO-1-N-1-induced bone destruction was inhibited by the administration of either anti-mouse or anti-human RANKL antibody. Bone destruction induced by the transplantation of human RANKL-overexpressing cells (HSC3-R2) was greatly inhibited by the injection of anti-human RANKL antibody. The present study revealed that RANKL produced by both stromal and cancer cells is involved in oral cancer-induced osteoclastic bone resorption. These results provide important information for understanding the cellular and molecular basis of cancer-associated bone destruction and the mechanism of action underlying RANKL antibody (denosumab) therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Sakai R.,Tokyo Medical and Dental University | Cho S.-K.,Tokyo Medical and Dental University | Cho S.-K.,Hanyang University | Nanki T.,Tokyo Medical and Dental University | And 46 more authors.
Arthritis Research and Therapy | Year: 2015

Introduction: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. Methods: This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. Results: Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). Conclusions: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice. © Sakai et al.

Yamazaki H.,Tokyo Medical and Dental University | Sakai R.,Tokyo Medical and Dental University | Koike R.,TMDU Hospital | Tanaka M.,Tokyo Medical and Dental University | And 19 more authors.
Journal of Rheumatology | Year: 2015

Objective. Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. Methods. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. Results. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p ≤ 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age > 65 years (HR 3.87, 95% CI 2.22-6.74), > 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if > 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Conclusion. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

Okamura E.,Tokyo Medical and Dental University | Suda N.,Meikai University | Baba Y.,Tokyo Medical and Dental University | Baba Y.,The Surgical Center | And 13 more authors.
Cleft Palate-Craniofacial Journal | Year: 2013

Objective: Ectrodactyly-ectodermal dysplasia-clefting syndrome is a congenital anomaly characterized by ectodermal dysplasia, ectrodactyly, cleft lip and palate, and lacrimal duct anomalies. Because this syndrome is frequently accompanied by a congenital lack of teeth, narrow palate, and malocclusion, comprehensive orthodontic intervention is required. Design: To highlight the specific dental and maxillofacial characteristics of ectrodactylyectodermal dysplasia-clefting syndrome, six Japanese individuals diagnosed with the syndrome are described here. Patients: The subjects consisted of two boys and four girls (age range, 6.0 to 13.9 years) diagnosed with ectrodactyly-ectodermal dysplasia-clefting syndrome by medical and dental specialists. Their conditions included ectodermal dysplasia (hypodontia, microdontia, enamel hypoplasia, and abnormalities in hair and nails), cleft lip and/or palate, and ectrodactyly. Cephalograms, panoramic x-rays, and dental casts were taken; systemic complications were recorded at the first visit to our dental hospital. Results: All individuals had severe oligodontia with 9 to 18 missing teeth. The missing teeth were mainly maxillary and mandibular incisors and second bicuspids, arranged in a symmetrical manner. Cephalometric analysis showed retruded and short maxilla due to cleft lip and/or palate. It is interesting that all individuals showed a characteristically shaped mandibular symphysis with a retruded point B. It is likely that this unusual symphyseal morphology is due to the lack of mandibular incisors. Conclusions: This study demonstrates the presence of severe oligodontia in the incisal and premolar regions and describes a characteristic maxillary and mandibular structure in Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting syndrome. © Copyright 2013 American Cleft Palate-Craniofacial Association.

Ng I.W.,Tokyo Medical and Dental University | Ng I.W.,International Research Center for Molecular Science in Tooth and Bone Diseases | Ono T.,Tokyo Medical and Dental University | Inoue-Arai M.S.,Tokyo Medical and Dental University | And 7 more authors.
Archives of Oral Biology | Year: 2012

Objective: To evaluate the spatio-temporal relationships between articulators in the anterior oral cavity, during the production of Japanese fricative and plosive articulation using our proposed method for tooth visualization in MR image sequences. Design: Ten healthy adults without malocclusion participated in the study. Customized maxillary and mandibular plates with space around the central incisors that was to be filled with MR-compatible contrast medium were made. During image-acquisition by a cine magnetic resonance imaging (MRI) technique, the subjects repeated vowel-consonant-vowel syllables (/asa/ and /ata/) without wearing the plates. The subjects then wore the plates for tooth imaging. All data were acquired in the midsagittal plane. Tooth boundaries were superimposed using landmarks. Several parameters and spatio-temporal changes in the centre of gravity (CoG) of the tongue were measured. Results: During /t/, the duration and amount of tongue-to-palate/incisor contact were significantly greater and the radius of the inscribed circle between the tongue-maxillary incisor-mandibular incisor was significantly shorter than those during /s/. /t/ also had a more anteriorly located CoG of the tongue than /s/ during maximum constriction. The spatio-temporal changes in the CoG of the tongue were significantly different between /asa/ and /ata/. Conclusions: We conclude that increased tongue-to-palate/incisor contact and greater anterior closure are necessary for the production of Japanese /t/ compared to /s/. With the use of this new method for tooth visualization in MR image sequences, it should be possible to evaluate the interaction of teeth and other articulators during speech. © 2011 Elsevier Ltd. All rights reserved.

Shimizu S.,Tokyo Medical and Dental University | Okuda N.,Tokyo Medical and Dental University | Kato N.,Tokyo Medical and Dental University | Rittling S.R.,Forsyth Institute | And 8 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. To investigate the molecular mechanisms underlying particle-induced osteolysis, we focused on osteopontin (OPN), a cytokine and cellattachment protein that is associated with macrophage chemoattractant and osteoclast activation. Methods. We compared OPN protein levels in human periprosthetic osteolysis tissues with those in osteoarthritis (OA) synovial tissues. To investigate the functions of OPN during particle-induced osteolysis in vivo, titanium particles were implanted onto the calvaria of OPN-deficient mice and their wild-type (WT) littermates. Mice were killed on day 10 and evaluated immunohistologically. The effects of OPN deficiency on the secretion of inflammatory cytokines were examined using cultured bone marrow-derived macrophages (BMMs). BMMs from OPN-deficient and WT mice were cultured with titanium particles for 12 hours, and the concentrations of inflammatory cytokines in the conditioned media were measured by enzyme-linked immunosorbent assay. Results. Expression of OPN protein was enhanced in human periprosthetic osteolysis tissues as compared with OA synovial tissues. In the particle-induced model of osteolysis of the calvaria, bone resorption was significantly suppressed by OPN deficiency via inhibition of osteoclastogenesis, whereas an inflammatory reaction was observed regardless of the genotype. Results of immunostaining indicated that OPN protein was highly expressed in the membrane and bone surface at the area of bone resorption in WT mice. When BMMs were exposed to titanium particles, the concentration of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1α (IL-1α), IL-1β, and IL-6, as well as chemotactic factors, such as monocyte chemoattractant protein 1 and macrophage inflammatory protein 1α, in the conditioned medium were significantly reduced by OPN deficiency. Whereas phagocytic activity of BMMs was not attenuated by OPN deficiency, phagocytosis-mediated NF-κB activation was impaired in OPN-deficient BMMs. These data indicated that OPN was implicated in the development of particleinduced osteolysis via the orchestration of pro-/antiinflammatory cytokines secreted from macrophages. Conclusion. OPN plays critical roles in wear debris-induced osteolysis, suggesting that OPN is a candidate therapeutic target for periprosthetic osteolysis. © 2010, American College of Rheumatology.

Haruyama N.,International Research Center for Molecular Science in Tooth and Bone Diseases | Hatakeyama J.,Biomedical Structures | Moriyama K.,International Research Center for Molecular Science in Tooth and Bone Diseases | B. Kulkarni A.,U.S. National Institutes of Health
Journal of Oral Biosciences | Year: 2011

Amelogenins are the most abundant extracellular matrix proteins secreted by ameloblasts during tooth development and are important for enamel formation. Recently, amelogenins have been detected not only in ameloblasts, which are differentiated from the epithelial cell lineage, but also in other tissues, including mesenchymal tissues at low levels, suggesting that amelogenins possess other functions in these tissues. The therapeutic application of an enamel matrix derivative rich in amelogenins resulted in the regeneration of cementum, alveolar bone, and periodontal ligament (PDL) in the treatment of experimental or human periodontitis, indicating the attractive potential of amelogenin in hard tissue formation. In addition, a full-length amelogenin (M180) and leucine-rich amelogenin peptide (LRAP) regulate cementoblast/PDL cell proliferation and migration in vitro. Interestingly, amelogenin null mice show increased osteoclasto-genesis and root resorption in periodontal tissues. Recombinant amelogenin proteins suppress osteoclasto-genesis in vivo and in vitro, suggesting that amelogenin is involved in preventing idiopathic root resorption. Amelogenins are implicated in tissue-specific epithelial-mesenchymal or mesenchymal-mesenchymal signaling ; however, the precise molecular mechanism has not been characterized. In this review, we first discuss the emerging evidence for the additional roles of M180 and LRAP as signaling molecules in mesenchymal cells. Next, we show the results of a yeast two-hybrid assay aimed at identifying protein-binding partners for LRAP We believe that gaining further insights into the signaling pathway modulated by the multifunctional amelogenin proteins will lead to the development of new therapeutic approaches for treating dental diseases and disorders.

Inoue G.,Tokyo Medical and Dental University | Nikaido T.,Tokyo Medical and Dental University | Sadr A.,Tokyo Medical and Dental University | Sadr A.,International Research Center for Molecular Science in Tooth and Bone Diseases | And 2 more authors.
Dental Materials Journal | Year: 2012

This study investigated the influence of the composition of self-etching primer adhesive systems on the morphology of acid-base resistant zones (ABRZs). One-step self-etching primer systems (Clearfil Tri-S Bond, G-Bond, and One-Up Bond F Plus) and two-step self-etching primer systems (Clearfil SE Bond, Clearfil Protect Bond, UniFil Bond, and Mac Bond II) were used in this study. Each adhesive was applied on prepared dentin disk surfaces, and a resin composite was placed between two dentin disks. All resin-bonded specimens were subjected to acid-base challenge. Observation under a scanning electron microscope (SEM) revealed the creation of an ABRZ adjacent to the hybrid layer for all the self-etch primer adhesive systems, even when non-fluoride releasing adhesives were used. The presence of fluoride in two-step self-etching adhesive significantly increased the thickness of ABRZ created. Results suggested that an ABRZ was created with the use of self-etching primer adhesive systems, but its morphology differed between oneand two-step self-etching primer adhesive systems and was influenced by fluoride release activity.

Yoshikawa T.,Tokyo Medical and Dental University | Wattanawongpitak N.,Naresuan University | Cho E.,Tokyo Medical and Dental University | Tagami J.,Tokyo Medical and Dental University | Tagami J.,International Research Center for Molecular Science in Tooth and Bone Diseases
Dental Materials Journal | Year: 2012

The aim of this study was to evaluate the effect of remaining dentin thickness (RDT) on resin composite bond strength to dentin surfaces when using various adhesive systems. One of three adhesives, Clearfil SE Bond, Single Bond or Clearfil Tri-S Bond, followed by Z100 resin composite were built up on flat dentin surfaces of human molars. The teeth were sectioned obtaining beams with crosssectional areas of approximately 1 mm2. RDT was measured and microtensile bond strength was determined. Resulting data were categorized into four groups: RDT<2 mm; 2≤RDT<3 mm; 3≤RDT<4 mm; RDT≥4 mm. Clearfil SE Bond showed a correlation between μTBS and RDT. Single Bond showed no significant difference in μTBS for any RDT. The bond strength of resin composite to the different RDT flat dentin surfaces was affected by the adhesive system used.

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