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Nakajima M.,RIKEN | Takahashi A.,RIKEN | Kou I.,RIKEN | Rodriguez-Fontenla C.,Hospital Clinico Universitario Of Santiago | And 18 more authors.
PLoS ONE | Year: 2010

Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ~4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10-8 for rs7775228 and 6.73×10-8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA. © 2010 Nakajima et al.


Kou I.,RIKEN | Takahashi A.,RIKEN | Urano T.,University of Tokyo | Urano T.,Saitama University | And 14 more authors.
PLoS ONE | Year: 2011

Osteoporosis is a common disease characterized by low bone mass, decreased bone quality and increased predisposition to fracture. Genetic factors have been implicated in its etiology; however, the specific genes related to susceptibility to osteoporosis are not entirely known. To detect susceptibility genes for osteoporosis, we conducted a genome-wide association study in Japanese using ~270,000 SNPs in 1,747 subjects (190 cases and 1,557 controls) followed by multiple levels of replication of the association using a total of ~5,000 subjects (2,092 cases and 3,114 controls). Through these staged association studies followed by resequencing and linkage disequilibrium mapping, we identified a single nucleotide polymorphism (SNP), rs7605378 associated with osteoporosis. (combined P = 1.51×10-8, odds ratio = 1.25). This SNP is in a previously unknown gene on chromosome 2q33.1, FONG. FONG is predicted to encode a 147 amino-acid protein with a formiminotransferase domain in its N-terminal (FTCD_N domain) and is ubiquitously expressed in various tissues including bone. Our findings would give a new insight into osteoporosis etiology and pathogenesis. © 2011 Kou et al.


Kumagai K.,Tsurumi University | Kumagai K.,Clinical Research Center for Rheumatology and Allergy | Hamada Y.,Tsurumi University | Gotoh A.,Yokohama Rosai Hospital | And 6 more authors.
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology | Year: 2010

Objective. This study aimed to elucidate the differences in antitumor immune responses between primary tumors and metastatic regional lymph nodes in head and neck squamous cell carcinoma (HNSCC). Study design. The clonality of tumor-infiltrating lymphocytes in tissue specimens from 17 HNSCC patients was examined regarding their T-cell receptor (TCR) repertoires and their complementary determining region 3 (CDR3) size spectratyping. Cytokine expression profiles and T-cell phenotypes also were measured by using real-time quantitative polymerase chain reaction. Results. The host immune responses to HNSCC cells, reflected by the TCR repertoire, differed between primary tumors and metastatic lymph nodes. CDS+-T cells and T helper type 1 (T H1)/T cytotoxic 1 (Tc1) cell cytokine production in metastatic and nonmetastatic lymph nodes were similar. Conclusions. The antitumor immune response to HNSCC cells changes during lymph node metastasis, and HNSCC cells can escape the cytotoxic immune responses mediated by CDB + -T cells and TH1/TC1 cells. These results suggest. that lymph node metastasis might be associated with changes in the nature of the primary tumor antigens. © 2010 Mosby, Inc. All rights reserved.


Kumagai K.,Tsurumi University | Hamada Y.,Tsurumi University | Holmlund A.B.,Karolinska Institutet | Gotoh A.,Yokohama Rosai Hospital | And 4 more authors.
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology | Year: 2010

Objective: This study aimed to investigate the level of vascular endothelial growth factor (VEGF) in the temporomandibular joint (TMJ) synovial fluid (SF) and the severity of arthroscopically observed synovitis before and after visually guided TMJ irrigation (VGIR) in patients with chronic closed lock (CCL). In addition, the findings were correlated with the clinical outcome. Study design: Twenty-four patients with unilateral CCL, who underwent a second VGIR either as a repeated therapeutic TMJ irrigation or as a follow-up arthroscopy, were enrolled in the study. They were divided into either successful (s-group; n = 11) and unsuccessful (u-group; n = 13) groups. The VEGF level in the aspirated SF and the severity of synovitis were compared between the s- and u-groups. In each group, the same parameters were compared before and after VGIR. The correlation of the VEGF level with the severity of synovitis was also studied. Results: At the first VGIR, the VEGF levels showed no significant differences when comparing s- and u-groups. At the second VGIR, the VEGF level was significantly higher in the u-group. The VEGF level significantly decreased after the first VGIR in the s-group but remained unchanged in the u-group. There was no significant correlation between the VEGF level and the severity of synovitis. Conclusions: The level of VEGF in TMJ SF seems to reflect the clinical status in patients with CCL. Moreover, VEGF may be an important target molecule in future chemotherapy of TMJ CCL. © 2010 Mosby, Inc. All rights reserved.


Wake M.,Tsurumi University | Wake M.,Clinical Research Center for Rheumatology and Allergy | Hamada Y.,Tsurumi University | Kumagai K.,Clinical Research Center for Rheumatology and Allergy | And 6 more authors.
British Journal of Oral and Maxillofacial Surgery | Year: 2013

Our aim was to explore important inflammatory mediators for synovial chondromatosis in the temporomandibular joints (TMJs) by analysing synovial fluid. Samples were collected from 10 patients with unilateral synovial chondromatosis of the TMJ. Control samples were obtained from 11 subjects with no symptoms in the TMJ. Concentrations of aggrecan, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8 (CXCL8), IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF)-A were measured in the samples of synovial fluid, and the results in the two groups compared. The tissues from the affected TMJ were examined histologically and immunohistochem-ically. Of the proteins evaluated, the concentrations of aggrecan, IL-6, and VEGF-A were significantly higher in the group with synovial chondromatosis. The immunohistochemical analysis showed that the synovial cells around the osteocartilaginous nodules were vigorously expressing VEGF-A. IL-6 and VEGF-A are thought to have important roles in the pathology of synovial chondromatosis of the TMJ. © 2012 The British Association of Oral and MaxilloFacial Surgeons. All rights reserved.

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