Sakae Tanaka

The University of Tokyo, Tōkyō, Japan

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Publications (202)832.85 Total impact

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    ABSTRACT: We examined the individual and combined effects of teriparatide and anti-RANKL (receptor activator of nuclear factor κB ligand) monoclonal antibody in ovariectomized mice. Three-month-old female C57BL/6 mice were ovariectomized (OVX) or sham operated. Four weeks after OVX, they were assigned to 3 different groups to receive anti-RANKL monoclonal antibody (Ab) alone (5 mg/kg single injection at 4 weeks after OVX, Ab group), teriparatide alone (80 μg/kg daily injection for 4 weeks from 4 weeks after OVX, PTH group), or mAb plus teriparatide (Ab + PTH group). Mice were sacrificed 8 weeks after OVX. Bone mineral density (BMD) was measured at the femur and lumbar spine. Hind limbs were subjected to histological and histomorphometric analysis. Serum osteocalcin and CTX-I levels were measured to investigate the bone turnover. Compared with Ab group, Ab + PTH group showed a significant increase in BMD at distal femur and femoral shaft. Cortical bone volume was significantly increased in PTH and Ab + PTH groups compared with Ab group. Bone turnover in Ab + PTH group was suppressed to the same degree as in Ab group. The number of TRAP-positive multinucleated cells was markedly reduced in Ab and Ab + PTH groups. These results suggest that combined treatment of teriparatide with anti-RANKL antibody has additive effects on BMD in OVX mice compared with individual treatment.
    06/2015; 2. DOI:10.1016/j.bonr.2014.12.002
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    ABSTRACT: The aim of this study was to clarify the prevalence and the predictive factors for undergoing total knee arthroplasty (TKA) among patients with rheumatoid arthritis (RA). The data of 1,134 patients with RA who were enrolled in the Japanese nationwide cohort database NinJa in 2003 and consecutively followed up until 2009 were analyzed. Seventy-six patients underwent TKA during the observation period. The yearly progression of the Modified Health Assessment Questionnaire (mHAQ) score from 2003 to 2004, but not the yearly progression of the Disease Activity Score in 28 Joints (DAS28) or patient visual analog scale (VAS) score, was significantly higher in the patients who underwent TKA than those who did not. Multivariate analysis showed that knee involvement in the disease, high Steinbrocker stage (III or IV), and high patient VAS score at the time of enrollment were powerful predictive factors, with hazard ratios of 4.01, 3.71, and 1.20, respectively. According to survival analysis with TKA as an endpoint, patients with knee involvement in the disease at the time of enrollment had a significantly worse 5-year survival rate than did those without knee involvement (83.5% vs 97.0%, respectively). Several factors were elucidated as predictive factors for undergoing TKA among patients with RA.
    Modern Rheumatology 05/2015; DOI:10.3109/14397595.2015.1045258 · 2.21 Impact Factor
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    ABSTRACT: The phosphorylated neurofilament heavy subunit (pNfH) is an axon fiber structural protein that is released into the cerebrospinal fluid (CSF) after nerve damage. Although previous studies have reported elevated CSF levels of pNfH in various neurological diseases, including amyotrophic lateral sclerosis, these levels have not been examined in patients with spinal stenosis. To investigate the CSF levels of pNfH in patients with lumbar spinal stenosis (LSS), and to examine the relationship between CSF levels of pNfH and the severity of LSS. A prospective observational study. We included consecutive patients with LSS who were undergoing myelography for preoperative evaluation. CSF samples from patients with idiopathic scoliosis were used as the controls. Physiological measures: CSF levels of pNfH were measured using an enzyme-linked immunosorbent assay. The Zurich Claudication Questionnaire (ZCQ) and the numerical rating scale (NRS) for sciatic pain were used to assess the clinical severity of LSS, and patients were grouped into tertiles according to their symptom severity and pain grading. Axial magnetic resonance imaging was used to evaluate the morphological severity of LSS, and patients were classified into 3 groups based on their morphological grading (using the CSF/rootlet ratio). Analysis of variance was used to examine the relationship between the CSF levels of pNfH and the severity of LSS. This work was supported by a grant from the Japanese Ministry of Health, Labour and Welfare, although there are no potential conflicts of interest to disclose. Thirty-three patients with LSS were included (13 men and 20 women; mean age, 73.2 years; range, 58-88 years). Most patients (n = 32) were positive for pNfH in their CSF (mean, 1,344 pg/mL; range, 149-9,250 pg/mL), while all control subjects were negative for pNfH in their CSF. Regarding the association with clinical severity, patients in the third tertiles of ZCQ and NRS tended to have higher levels of pNfH compared to the other groups. There was no association between the CSF level of pNfH and the morphological severity of LSS. This study detected elevated pNfH levels in the CSF of patients with LSS. Patients with severe clinical symptoms were more likely to exhibit high levels of pNfH. Our results indicate the potential usefulness of pNfH as a biomarker for compressive spinal disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    The spine journal: official journal of the North American Spine Society 03/2015; DOI:10.1016/j.spinee.2015.03.013 · 2.80 Impact Factor
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    ABSTRACT: The use of larger femoral heads to prevent the dislocation of artificial hip joints has recently become more common. However, concerns about the subsequent use of thinner polyethylene liners and their effects on wear rate have arisen. Previously, we prepared and evaluated the biological and mechanical effects of a novel highly crosslinked polyethylene (CLPE) liner with a nanometer-scaled graft layer of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). Our findings showed that the PMPC-grafted particles were biologically inert and caused no subsequent bone resorptive responses and that the PMPC-grafting markedly decreased wear in a hip joint simulator. However, the metal or ceramic femoral heads used in this previous study had a diameter of 26 mm. Here, we investigated the wear-resistance of the PMPC-grafted CLPE liner with a 40-mm femoral head during 10 × 10(6) cycles of loading in the hip joint simulator. The results provide preliminary evidence the grafting markedly decreased gravimetric wear rate and the volume of wear particles, even when coupled with larger femoral heads. Thus, we believe the PMPC-grafting will prolong artificial hip joint longevity both by preventing aseptic loosening and by improving the stability of articular surface. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Orthopaedic Research 03/2015; DOI:10.1002/jor.22868 · 2.97 Impact Factor
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    ABSTRACT: Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT);Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
    Proceedings of the National Academy of Sciences 03/2015; 112(10). DOI:10.1073/pnas.1419699112 · 9.81 Impact Factor
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    ABSTRACT: The objective of the present study was to clarify the association of joint space narrowing with knee pain in Japanese men and women using a large-scale population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. This study examined the association between minimum joint space width (mJSW) in the medial compartment and pain at the knee. mJSW was measured in the medial and lateral compartments of the knee using a knee OA computer-aided diagnosis system. From the 3,040 participants in the ROAD study, the present study analyzed 2,733 participants who completed the radiographic examinations and questionnaires regarding knee pain (975 men and 1,758 women; mean age, 69.9±11.2 years). Subjects with lateral knee OA were excluded. After adjustment for age and BMI, medial mJSW, as well as medial mJSW/lateral mJSW, was significantly associated with knee pain. Sex and BMI affected the association of medial mJSW with knee pain. The threshold of medial mJSW was approximately 3 mm in men and 2 mm in women, while that of medial mJSW/lateral mJSW was approximately 60% in both men and women. Body mass index was found to have a distinct effect on the association of mJSW with pain. The present cross-sectional study using a large-scale population from the ROAD study showed that joint space narrowing had a significant association with knee pain. The thresholds of joint space narrowing for knee pain were also established. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
    Osteoarthritis and Cartilage 01/2015; DOI:10.1016/j.joca.2015.01.011 · 4.66 Impact Factor
  • IEEE/ASME Transactions on Mechatronics 01/2015; DOI:10.1109/TMECH.2015.2410287 · 3.65 Impact Factor
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    ABSTRACT: CCAAT/enhancer-binding protein (C/EBP) β regulates chondrocyte differentiaion and proliferation during endochondral ossification. However, expression and function of other C/EBP family members in chondrocytes have not been fully understood. To understand the comprehensive regulation of chondrocyte differentiation by C/EBPs, we initially examined their expression levels. Among four members (C/EBPα, C/EBPβ, C/EBPδ and C/EBPε) with transactivation domain, expression of Cebpb and Cebpd was abundant compared to Cebpa, while Cebpe was hardly expressed in mouse isolated chondrocytes. Doxycycline (DOX)-inducible overexpression of each of the three C/EBPs (C/EBPα, C/EBPβ and C/EBPδ) in ATDC5 cells suppressed expressions of early differentiation markers including Col2a1, aggrecan and Sox9, enhanced those of late differentiation markers including Mmp13, Vegfa and Col10a1, and decelerated cell proliferation, indicating their overlapped functions in chondrocytes. In contrast, DOX-inducible overexpression of A-CEBP, which exerts a dominant-negative effect against all C/EBPs, increased expressions of early differentiation markers and decreased those of late differentiation markers. Finally, microarray and gene ontology analyses showed that A-CEBP altered many genes related with various events or tissues such as skeletal development, cartilage, cell cycle, inflammation and apoptosis. In conclusion, C/EBPα, C/EBPβ and C/EBPδ regulate proliferation and differentiation of chondrocytes and possibly is involved with apoptosis and inflammation. C/EBPs may play a variety of roles in the homeostasis of joint cartilage under physiological and pathological conditions.
    Biomedical research (Tokyo, Japan) 01/2015; 36(1):21-9. DOI:10.2220/biomedres.36.21 · 1.10 Impact Factor
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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. DOI:10.1371/journal.pone.0115169 · 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. DOI:10.1371/journal.pone.0115400 · 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; DOI:10.3109/14397595.2014.997424 · 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; 83(4). DOI:10.1016/j.wneu.2014.12.019 · 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. We measured the alignment of the tibial cutting guides, the first-cut cutting surfaces and the second cut cutting surfaces using the navigation system in 50 UKAs. Cutting error was defined as the angular difference between the cutting guide and cutting surface. The mean absolute first-cut cutting error was 1.9° (1.1° varus) in the coronal plane and 1.1° (0.6° anterior slope) in the sagittal plane, whereas the mean absolute second-cut cutting error was 1.1° (0.6° varus) in the coronal plane and 1.1° (0.4° anterior slope) in the sagittal plane. Cutting the tibia horizontally twice reduced the cutting errors in the coronal plane significantly (P<0.05). Our study demonstrated that in UKA, cutting the tibia horizontally twice using the same cutting guide reduced cutting error in the coronal plane. Copyright © 2014 Elsevier B.V. All rights reserved.
    The Knee 12/2014; DOI:10.1016/j.knee.2014.11.015 · 1.70 Impact Factor
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    ABSTRACT: The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)−3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 12/2014; 92(12). DOI:10.1002/jnr.23448 · 2.73 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; 15(4). DOI:10.1016/j.spinee.2014.11.012 · 2.80 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; DOI:10.3109/14397595.2014.972607 · 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; 455(3-4). DOI:10.1016/j.bbrc.2014.11.009 · 2.28 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; DOI:10.1053/j.jfas.2014.09.027 · 0.98 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; 20(1). DOI:10.1007/s00776-014-0669-1 · 1.01 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; 30(5). DOI:10.1002/jbmr.2418 · 6.59 Impact Factor

Publication Stats

7k Citations
832.85 Total Impact Points


  • 1997–2015
    • The University of Tokyo
      • • Department of Orthopaedic Surgery and Spinal Surgery
      • • Division of Sensory and Motor System Medicine
      • • School of Medicine
      Tōkyō, Japan
    • Tokyo Metropolitan Institute of Medical Science
      Edo, Tōkyō, Japan
  • 2009–2014
    • Tokyo Medical University
      • Department of Orthopedic Surgery
      Edo, Tōkyō, Japan
  • 2004–2014
    • Sagamihara National Hospital
      Йокосука, Kanagawa, Japan
  • 2012
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
  • 1992–2009
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan
  • 2005
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
  • 1996–2004
    • Yale University
      • Department of Cell Biology
      New Haven, Connecticut, United States
  • 2003
    • Matsumoto Dental University
      • Institute for Oral Science
      Matsumoto, Nagano-ken, Japan