Sakae Tanaka

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (181)649.65 Total impact

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    ABSTRACT: Transcription factors SOX9, SOX5 and SOX6 are indispensable for generation and differentiation of chondrocytes. However, molecular mechanisms to induce the SOX genes are poorly understood. To address this issue, we previously determined the human embryonic enhancer of SOX6 by 5'RACE analysis, and identified the 46-bp core enhancer region (CES6). We initially performed yeast one-hybrid assay for screening other chondrogenic factors using CES6 as bait, and identified a zinc finger protein ZNF449. ZNF449 and Zfp449, a counterpart in mouse, transactivated enhancers or promoters of SOX6, SOX9 and COL2A1. Zfp449 was expressed in mesenchyme-derived tissues including cartilage, calvaria, muscle and tendon, as well as in other tissues including brain, lung and kidney. In limb cartilage of mouse embryo, Zfp449 protein was abundantly located in periarticular chondrocytes, and decreased in accordance with the differentiation. Zfp449 protein was also detected in articular cartilage of an adult mouse. During chondrogenic differentiation of human mesenchymal stem cells, ZNF449 was increased at an early stage, and its overexpression enhanced SOX9 and SOX6 only at the initial stage of the differentiation. We further generated Zfp449 knockout mice to examine the in vivo roles; however, no obvious abnormality was observed in skeletal development or articular cartilage homeostasis. ZNF449 may regulate chondrogenic differentiation from mesenchymal progenitor cells, although the underlying mechanisms are still unknown.
    PLoS ONE 12/2014; 9(12):e115169. · 3.53 Impact Factor
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    ABSTRACT: Schwann cells are an important cell source for regenerative therapy for neural disorders. We investigated the role of the transcription factor sex determining region Y (SRY)-box 10 (SOX10) in the proliferation and myelination of Schwann cells. SOX10 is predominantly expressed in rat sciatic nerve-derived Schwann cells and is induced shortly after birth. Among transcription factors known to be important for the differentiation of Schwann cells, SOX10 potently transactivates the S100B promoter. In cultures of Schwann cells, overexpressing SOX10 dramatically induces S100B expression, while knocking down SOX10 with shRNA suppresses S100B expression. Here, we identify three core response elements of SOX10 in the S100B promoter and intron 1 with a putative SOX motif. Knockdown of either SOX10 or S100B enhances the proliferation of Schwann cells. In addition, using dissociated cultures of dorsal root ganglia, we demonstrate that suppressing S100B with shRNA impairs myelination of Schwann cells. These results suggest that the SOX10-S100B signaling axis critically regulates Schwann cell proliferation and myelination, and therefore is a putative therapeutic target for neuronal disorders.
    PLoS ONE 12/2014; 9(12):e115400. · 3.53 Impact Factor
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    ABSTRACT: Abstract Objectives The aim of this study was to estimate the effect of fondaparinux and enoxaparin combined with mechanical prophylaxis (MP) after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We also investigated the occurrence of pulmonary embolism (PE) and associated risk factors. Methods Data were retrospectively collected on patients who underwent THA or TKA between 2008 and 2010 from the Japanese Diagnosis Procedure Combination database (n=49,678). We extracted information on sex, age, main diagnosis, types of anesthesia, duration of anesthesia, comorbidities, hospital volume, the use of MP, and the use of anticoagulant drugs. Results The overall occurrence of PE was 0.41%. Multivariate logistic regression analysis showed that the occurrence of PE was significantly higher in females (odds ratio, 2.17; p<0.001, compared with males), TKA (1.47; p=0.039, compared with THA), and longer-duration anesthesia (2.63; p=0.008 in the ≥240-min. group compared with the ≤119-min. group). Compared with the MP-alone group, the occurrence of PE was significantly reduced in the fondaparinux group (0.58; p=0.025) and the enoxaparin group (0.59; p=0.046). Conclusions Fondaparinux or enoxaparin combined with MP decreased the occurrence of PE. The risk factors for PE were female patients, TKA, and longer-duration anesthesia (≥240 min.).
    Modern Rheumatology 12/2014; · 2.21 Impact Factor
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    ABSTRACT: The objectives of this study are to examine in-hospital mortality and postoperative major complications in patients undergoing fusion surgery for atlantoaxial subluxation (AAS) and to examine whether the risk of perioperative complications varies between rheumatoid arthritis (RA) patients and non-RA patients. A retrospective analysis of data from the Diagnosis Procedure Combination database, a nationwide administrative impatient database in Japan, identified 1,090 patients who underwent spinal fusion surgery for AAS during 2007-2012. Patients' clinical characteristics were extracted, including age, sex, use of homologous blood transfusion, length of stay, and type of hospital. Clinical outcomes included in-hospital death and major complications including surgical site infection, sepsis, cardiac events, respiratory disorders, acute renal failure, pulmonary embolism, perioperative stroke, and vertebral injury. Massive blood transfusion was defined as at least 6 units of red blood cells. Four hundred and sixty-five patients (42.7%) were classified as the RA group. In-hospital mortality following fusion surgery for AAS was 0.5% (5/1090), and major complications occurred in 5% (55/1090). Multivariate analyses showed that RA patients were more likely to have major complications after surgery than non-RA patients (odds ratio: 1.69; 95% confidence interval: 0.96-2.97; p=0.07) and the rate of massive blood transfusion was significantly higher in RA patients than in non-RA patients (odds ratio: 2.29; 95% confidence interval: 1.12-4.68; p=0.02). The in-hospital mortality following fusion surgery for AAS was relatively low. However, RA patients had an increased risk of postoperative complications and massive blood transfusion compared with non-RA patients. Copyright © 2014 Elsevier Inc. All rights reserved.
    World Neurosurgery 12/2014; · 2.42 Impact Factor
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    ABSTRACT: Bone cutting error can be one of the causes of malalignment in unicompartmental knee arthroplasty (UKA). The amount of cutting error in total knee arthroplasty has been reported. However, none have investigated cutting error in UKA. The purpose of this study was to reveal the amount of cutting error in UKA when open cutting guide was used and clarify whether cutting the tibia horizontally twice using the same cutting guide reduced the cutting errors in UKA.
    The Knee 12/2014; · 2.01 Impact Factor
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    ABSTRACT: We have previously reported that transforming growth factor β (TGF-β) plays an essential role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the detailed underlying molecular mechanisms still remain unclear. Formaldehyde-assisted isolation of regulatory elements and chromatin immunoprecipitation followed by sequencing (FAIRE-seq and ChIP-seq) analyses indicated the cooperation of Smad2/3 with c-Fos during osteoclastogenesis. Biochemical analysis and immunocytochemical analysis revealed that physical interaction between Smad2/3 and c-Fos is required for their nuclear translocation. The gene expression of Nfatc1, a key regulator of osteoclastogenesis, was regulated by RANKL and TGF-β, and c-Fos binding to open chromatin sites was suppressed by inhibition of TGF-β signaling by SB431542. Conversely, Smad2/3 binding to Nfatc1 was impaired by c-Fos deficiency. These results suggest that TGF-β regulates RANKL-induced osteoclastogenesis through reciprocal cooperation between Smad2/3 and c-Fos. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; · 6.04 Impact Factor
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    ABSTRACT: Disc degeneration (DD) reportedly causes low back pain (LBP) and is often observed concomitantly with endplate signal change (ESC) and/or Schmorl's node (SN) on magnetic resonance imaging (MRI). To examine the association between DD and LBP, considering ESC and/or SN presence, in a large population study. Cross-sectional, population-based study in 2 regions of Japan PARTICIPANT SAMPLE: Of 1011 possible participants, data from 975 participants (324 men, 651 women; mean age, 66.4 years; range, 21-97 years) were included. Prevalence of DD, ESC, and SN alone and in combination in the lumbar region, and the association of these prevalence levels with LBP. This study was funded by Japanese Grant-in-Aid for Scientific Research. There is no conflict of interest. Sagittal T2-weighted images were used to assess the intervertebral spaces between L1/2 and L5/S1. DD was classified using the Pfirrmann classification system (grade 4 and 5 indicated degeneration); ESC was defined as a diffuse high-signal change along either area of the endplate, and SN was defined as a small well-defined herniation pit with a surrounding wall of hypointense signal. Logistic regression analysis was used to determine the odds ratios (OR) and confidence intervals (CI) for LBP in the presence of radiographic changes in the lumbar region and at each lumbar intervertebral level, compared to patients without radiographic change, after adjusting for age, body mass index, and sex. The prevalence of lumbar structural findings was as follows: DD alone, 30.4%; ESC alone, 0.8%; SN alone, 1.5%; DD and ESC, 26.6%; DD and SN, 12.3%; and DD, ESC, and SN, 19.1%. These lumbar structural findings were significantly associated with LBP in the lumbar region overall, as follows: DD, ESC, and SN, OR 2.17, 95% CI 1.2-3.9; L1/2, OR 6.00, 95% CI 1.9-26.6; L4/5, OR 2.56, 95% CI 1.4-4.9; and L5/S1, OR 2.81, 95% CI, 1.1-2.3. The combination of DD and ESC was significantly associated with LBP as follows: L3/4, OR 2.43, 95% CI 1.5-4.0; L4/5, OR 1.82, 95% CI 1.2-2.8; L5/S1, OR 1.60, 95% CI 1.1-2.3. Our data suggest that DD alone is not associated with LBP. By contrast, the combination of DD and ESC was highly associated with LBP. Copyright © 2014 Elsevier Inc. All rights reserved.
    The spine journal: official journal of the North American Spine Society 11/2014; · 2.90 Impact Factor
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    ABSTRACT: Objective. This study aimed to assess the mutual associations between musculoskeletal diseases (knee osteoarthritis [KOA], lumbar spondylosis [LS], osteoporosis [OP]) and metabolic syndrome components (obesity [OB], hypertension [HT], dyslipidemia [DL], impaired glucose tolerance [IGT]). Methods. Of the 1,690 participants (596 men, 1,094 women) at baseline, 1,384 individuals (81.9%; 466 men, 918 women) had complete data at the first follow-up in 2008. Logistic regression analysis included the occurrence or nonoccurrence of the musculoskeletal diseases or metabolic components as the outcome variable and the remaining musculoskeletal diseases and metabolic components at baseline as explanatory variables, adjusted for age, sex, residential region, smoking, and alcohol consumption. Results. The risk of KOA occurring increased significantly with HT (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.22–5.42; p = 0.013) and IGT (OR, 1.99; 95%CI, 1.07–3.70; p = 0.029). The risk of OP occurring at the lumbar spine increased with OP at the femoral neck (OR, 4.21; 95%CI 1.46–12.1; p = 0.008), and vice versa (OR, 2.19; 95%CI, 1.01–479; p = 0.047). KOA increased the risk of HT (Kellgren–Lawrence [KL] grade = 0, 1 vs. KL = 2: OR, 1.84; 95%CI, 1.09–3.12; p = 0.024) and DL (KL = 0, 1 vs. KL ≥ 3: OR, 1.66; 95%CI, 1.05–2.61; p = 0.029) occurring. Reciprocal relationships existed between the presence of metabolic components and the occurrence of the other metabolic components. Conclusion. Mutual relationships existed between the occurrence and presence of musculoskeletal diseases, particularly KOA, and metabolic syndrome components.
    Modern Rheumatology 11/2014; · 2.21 Impact Factor
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    ABSTRACT: Gene expression is dependent not only on genomic sequences, but also epigenetic control, in which the regulation of chromatin by histone modification plays a crucial role. Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) are related to transcriptionally activated and silenced sequences, respectively. Osteoclasts, the multinucleated cells that resorb bone, are generated by the fusion of precursor cells of monocyte/macrophage lineage. To elucidate the molecular and epigenetic regulation of osteoclast differentiation, we performed a chromatin immunoprecipitation sequencing (ChIP-seq) analysis for H3K4me3 and H3K27me3 in combination with RNA sequencing. We focused on the histone modification change from H3K4me3(+)H3K27me3(+) to H3K4me3(+)H3K27me3(–) and identified the protocadherin-7 gene (Pcdh7) to be among the genes epigenetically regulated during osteoclastogenesis. Pcdh7 was induced by RANKL stimulation in an NFAT-dependent manner. The knockdown of Pcdh7 inhibited RANKL-induced osteoclast differentiation due to the impairment of cell–cell fusion, accompanied by a decreased expression of the fusion-related genes Dcstamp, Ocstamp and Atp6v0d2. This study demonstrates that Pcdh7 plays a key role in osteoclastogenesis by promoting cell–cell fusion.
    Biochemical and Biophysical Research Communications 11/2014; · 2.28 Impact Factor
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    ABSTRACT: Spinal cord injury (SCI) is a serious clinical problem that suddenly deprives patients of neurologic function and drastically diminishes their quality of life. Gene introduction has the potential to be effective for various pathological states of SCI because various proteins can be produced just by modifying nucleic acid sequences. In addition, the sustainable protein expression allows to maintain its concentration at an effective level at the target site in the spinal cord. Here we propose an approach using a polyplex system composed of plasmid DNA (pDNA) and a cationic polymer, poly{N′-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)], that has high capacity to promote endosome escape and the long-term safety by self-catalytically degrading within a few days. We applied brain-derived neurotrophic factor (BDNF)-expressing pDNA for SCI treatment by intrathecal injection of PAsp(DET)/pDNA polyplex. A single administration of polyplex for experimental SCI provided sufficient therapeutic effects including prevention of neural cell death and enhancement of motor function recovery. This lasted for a few weeks after SCI, demonstrating the capability of this system to express BDNF in a safe and responsible manner for treatment of various pathological states in SCI.
    Journal of Controlled Release 11/2014; · 7.63 Impact Factor
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    ABSTRACT: Surgical site infection is a serious and significant complication after spinal surgery and is associated with high morbidity rates, high healthcare costs and poor patient outcomes. Accurate identification of risk factors is essential for developing strategies to prevent devastating infections. The purpose of this study was to identify independent risk factors for surgical site infection among posterior thoracic and/or lumbar spinal surgery in adult patients using a prospective multicenter surveillance research method.
    Journal of Orthopaedic Science 11/2014; · 1.01 Impact Factor
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    ABSTRACT: A 45-year-old man sustained an Achilles tendon rupture while playing futsal. A concomitant medial malleolar fracture was not diagnosed until the patient underwent an operation for Achilles tendon repair. A routine postoperative radiograph showed a minimally displaced medial malleolar fracture. Conservative treatment was chosen for the fracture. The function of the Achilles tendon recovered well, and the fracture was united. A medial malleolar fracture can be missed when an Achilles tendon rupture occurs simultaneously. Thus, surgeons should consider the possibility of medial malleolar fracture associated with an Achilles tendon rupture. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.
    The Journal of foot and ankle surgery: official publication of the American College of Foot and Ankle Surgeons 11/2014;
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    ABSTRACT: Patient satisfaction with posterior laminoplasty for cervical compression myelopathy is not yet established. Moreover, postoperative patient-reported outcomes (PROs) associated with patient satisfaction remain unclear. This study aimed to investigate patient satisfaction after double-door laminoplasty for cervical compression myelopathy, and to identify the postoperative patient-reported outcomes associated with patient satisfaction.
    Journal of Orthopaedic Science 10/2014; · 1.01 Impact Factor
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    ABSTRACT: Modifying the surface and substrate of a crosslinked polyethylene (CLPE) liner may be beneficial for high wear resistance as well as high oxidative stability and excellent mechanical properties, which would be useful in contributing to the long-term performance of orthopaedic bearings. A grafted poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) layer on a vitamin E-blended crosslinked PE (HD-CLPE[VE]) surface may provide hydrophilicity and lubricity without compromising the oxidative stability or mechanical properties.
    Clinical Orthopaedics and Related Research 10/2014; · 2.88 Impact Factor
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    ABSTRACT: In this study, we aimed to determine whether the outcomes of total hip arthroplasty (THA) after rotational acetabular osteotomy (RAO) are equal to those of primary THA, and to elucidate the characteristics of THA after RAO. The clinical and radiographic findings of THA after RAO (44 hips), with minimum 24 months follow-up, were compared with a matched control group of 58 hips without prior RAO. We found that the outcomes in terms of functional scores and complication rates did not differ between THA after RAO and THA without previous pelvic osteotomy, indicating that the results of THA after RAO are equivalent to those of primary THA. Although THA after RAO requires technical considerations, similar clinical outcomes to primary THA can be expected.
    The Journal of Arthroplasty 10/2014; · 2.37 Impact Factor
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    ABSTRACT: The population of elderly individuals who need nursing care is rapidly increasing in Japan. Locomotive syndrome involves a decrease in mobility due to locomotive organ dysfunction, and increases risk for dependency on nursing care service. Because gait speed and chair stand time are correlated with such risks, patients with locomotive syndrome are assessed using brief methods such as the two-step test, which involves dividing the maximum stride length by the height of the patient, and the stand-up test, which involves standing on one or both legs at different heights. One leg standing and squatting are recommended as beneficial locomotive home exercises. Locomotive syndrome has been recognized widely in Japan, and included in the National Health Promotion Movement (2013-2022).
    Nihon rinsho. Japanese journal of clinical medicine. 10/2014; 72(10):1715-20.
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    ABSTRACT: Recently, remnant-preserving anterior cruciate ligament (ACL) reconstruction has been increasingly performed to achieve revascularization, cell proliferation, and recovery of high-quality proprioception. However, poor arthroscopic visualization makes accurate socket placement during remnant-preserving ACL reconstruction difficult. This study describes a surgical technique used to create an anatomical femoral socket with a three-dimensional (3D) fluoroscopy based navigation system during technically demanding remnant-preserving ACL reconstruction.
    Knee surgery & related research. 09/2014; 26(3):168-76.
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    ABSTRACT: Necrotising soft-tissue infections (NSTIs) of the upper limb are uncommon, but potentially life-threatening. We used a national database to investigate the risk factors for amputation of the limb and death. We extracted data from the Japanese Diagnosis Procedure Combination database on 116 patients (79 men and 37 women) who had a NSTI of the upper extremity between 2007 and 2010. The overall in-hospital mortality was 15.5%. Univariate analysis of in-hospital mortality showed that the significant variables were age (p = 0.015), liver dysfunction (p = 0.005), renal dysfunction (P < 0.001), altered consciousness (p = 0.049), and sepsis (p = 0.021). Logistic regression analysis showed that the factors associated with death in hospital were age over 70 years (Odds Ratio (OR) 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR 15.4; 95% CI 3.8 to 62.8; p < 0.001). Univariate analysis of limb amputation showed that the significant variables were diabetes (p = 0.017) mellitus and sepsis (p = 0.001). Multivariable logistic regression analysis showed that the factors related to limb amputation were sepsis (OR 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR 1.6; 95% CI 1.1 to 21.1; p = 0.038). For NSTIs of the upper extremity, advanced age and renal dysfunction are both associated with a higher rate of in-hospital mortality. Sepsis and diabetes mellitus are both associated with a higher rate of amputation.
    Journal of Bone and Joint Surgery - British Volume 08/2014; 96-B:1530-4. · 2.80 Impact Factor
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    ABSTRACT: Object Despite its potential clinical impact, information regarding progression of thoracic ossification of the posterior longitudinal ligament (OPLL) is scarce. Posterior decompression with stabilization is currently the primary surgical treatment for symptomatic thoracic OPLL; however, it remains unclear whether thoracic OPLL increases in size following spinal stabilization. It is also unknown whether patients' clinical symptoms worsen as OPLL size increases. In this retrospective case series study, the authors examined the postoperative progression of thoracic OPLL. Methods Nine consecutive patients with thoracic OPLL who underwent posterior decompression and fixation with a minimum follow-up of 3 years were included in this study. Thin-slice CT scans of the thoracic spine obtained at the time of surgery and the most recent follow-up were analyzed. The level of the most obvious protrusion of ossification was determined using the sagittal reconstructions, and the ossified area was measured on the axial reconstructed scan at the level of the most obvious protrusion of ossification using the DICOM (digital imaging and communications in medicine) software program. Myelopathy severity was assessed according to the Japanese Orthopaedic Association (JOA) scale score for lower-limb motor function on admission, at postoperative discharge, and at the last follow-up visit. Results The OPLL area was increased in all patients. The mean area of ossification increased from 83.6 ± 25.3 mm (2) at the time of surgery to 114.8 ± 32.4 mm (2) at the last follow-up visit. No patients exhibited any neurological deterioration due to OPLL progression. Conclusions The present study demonstrated that the size of the thoracic OPLL increased after spinal stabilization. Despite diminished local spinal motion, OPLL progression did not decrease or stop. Physicians should pay attention to ossification progression in patients with thoracic OPLL.
    Journal of Neurosurgery Spine 08/2014; · 2.36 Impact Factor
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    ABSTRACT: Objectives. This study aimed to evaluate the clinical safety and wear-resistance of the novel highly cross-linked polyethylene (HXLPE) acetabular liner with surface grafting of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) at 3 years after total hip replacement (THR). Methods. Eighty consecutive patients underwent cementless THR using a 26-mm diameter cobalt-chromium-molybdenum alloy femoral head and a PMPC-grafted HXLPE liner for the bearing couplings. We evaluated the clinical and radiographic outcomes of 76 patients at 3 years after the index surgery. Results. The clinical results at 3 years were equivalent to a Harris hip score of 95.6 points. No adverse events were associated with the implanted PMPC-grafted HXLPE liner, and no periprosthetic osteolysis was detected. The mean femoral head penetration rate was 0.002 mm/year, representing marked reduction compared with other HXLPE liners. Conclusions. A PMPC-grafted HXLPE liner is a safe option in THR and probably reduces the generation of wear particles.
    Modern Rheumatology 08/2014; · 2.21 Impact Factor

Publication Stats

5k Citations
649.65 Total Impact Points


  • 1997–2014
    • The University of Tokyo
      • • Department of Orthopaedic Surgery and Spinal Surgery
      • • Department of Surgical Sciences
      • • Division of Sensory and Motor System Medicine
      Edo, Tōkyō, Japan
  • 2013
    • Kanto Rosai Hospital
      Kawasaki Si, Kanagawa, Japan
  • 2011–2012
    • Jichi Medical University
      • Department of Orthopaedic Surgery
      Totigi, Tochigi, Japan
  • 2010–2012
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
  • 2009–2012
    • Tokyo Medical University
      • • Division of Rheumatology
      • • Department of Orthopedic Surgery
      Edo, Tōkyō, Japan
  • 2006–2012
    • Tokyo Medical and Dental University
      • Department of Cell Signaling
      Edo, Tōkyō, Japan
    • Tokyo Metropolitan Komagome Hospital
      Edo, Tōkyō, Japan
  • 2005
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
  • 2004
    • Sagamihara National Hospital
      Йокосука, Kanagawa, Japan
  • 2003–2004
    • Yale University
      • Department of Cell Biology
      New Haven, CT, United States
    • Matsumoto Dental University
      • Institute for Oral Science
      Matsumoto, Nagano-ken, Japan
  • 1992–1997
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan