Sakae Tanaka

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (154)546.62 Total impact

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    ABSTRACT: Pulmonary embolism (PE) is recognized as an important complication in patients undergoing hip fracture surgery. However, clinical evidence demonstrating the effectiveness of pharmacological thromboprophylaxis, including fondaparinux, is limited because the occurrence of postoperative PE after hemiarthroplasty is very low. The goal of this study was to analyze the effect of fondaparinux in reducing PE following hemiarthroplasty for femoral neck fracture using large-scale retrospective data.
    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 07/2014;
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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 07/2014; · 2.97 Impact Factor
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    ABSTRACT: The aim of this study was to examine the clinical characteristics of rheumatoid arthritis (RA) patients who underwent cervical spine surgery using a multicenter observational database.
    BMC Musculoskeletal Disorders 06/2014; 15(1):203. · 1.88 Impact Factor
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    ABSTRACT: The objective of the present longitudinal study was to clarify whether osteophytosis and joint space narrowing predict quality of life (QOL) decline using a longitudinal population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. The present study analyzed 1,525 participants who completed the radiographic examination at baseline and questionnaires regarding QOL at a 3-year follow-up (546 men and 979 women; mean age, 67.0 ± 11.0 years). This study examined the associations of osteophyte area (OPA) and minimum joint space width (mJSW) in the medial compartment of the knee at baseline with pain and physical functional disability measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). OPA and mJSW in the medial compartment of the knee were measured using a knee osteoarthritis (OA) computer-aided diagnosis system. Overall, OPA independently predicted physical functional disability after 3 years of follow-up. When analyzed in men and women separately, OPA, rather than mJSW, was an independent predictor for pain and physical functional disability after 3 years of follow-up in men. OPA, rather than mJSW, also predicted worsening of pain in men during the 3-year follow-up, whereas in women, mJSW, rather than OPA, predicted worsening of pain. In conclusion, the present longitudinal study using a large-scale population from the ROAD study found gender differences in the association of osteophytosis and joint space narrowing with pain and physical functional disability.
    Clinical rheumatology. 05/2014;
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    ABSTRACT: The ultimate goal in manipulating the surface and substrate of a cross-linked polyethylene (CLPE) liner is to obtain not only high wear resistance but also high oxidative stability and high-mechanical properties for life-long orthopedic bearings. We have demonstrated the fabrication of highly hydrophilic and lubricious poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) grafting layer onto the antioxidant vitamin E-blended CLPE (HD-CLPE(VE)) surface. The PMPC grafting layer with a thickness of 100 nm was successfully fabricated on the vitamin E-blended CLPE surface by using photoinduced-radical graft polymerization. Since PMPC has a highly hydrophilic nature, the water wettability and lubricity of the PMPC-grafted CLPE and HD-CLPE(VE) surfaces were greater than that of the untreated CLPE surface. The PMPC grafting contributed significantly to wear reduction in a hip-joint simulator wear test. Despite high-dose gamma-ray irradiation for cross-linking and further UV irradiation for PMPC grafting, the substrate modified by vitamin E blending maintained high-oxidative stability because vitamin E is an extremely efficient radical scavenger. Furthermore, the mechanical properties of the substrate remained almost unchanged even after PMPC grafting or vitamin E blending, or both PMPC grafting and vitamin E blending. In conclusion, the PMPC-grafted HD-CLPE(VE) provided simultaneously high-wear resistance, oxidative stability, and mechanical properties.
    Biomaterials 05/2014; · 7.60 Impact Factor
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    ABSTRACT: Introduction Microendoscopic techniques through a unilateral paramedian approach or muscle-preserving techniques using a microscope have been reported as minimally invasive spinal decompression procedures for the cervical spine. In this study, we developed a novel technique, cervical microendoscopic interlaminar decompression (CMID) through a midline approach, for treating cervical compression myelopathy. Methods A total of 29 consecutive patients with single- or two-level cervical compression myelopathy were reviewed. For the single-level cases (e.g., C5-C6), a midline skin incision, ∼ 2 cm in length, was made at the spinal level to be decompressed (C5-C6) under fluoroscopic guidance. The nuchal ligament was longitudinally cut, and tips of the spinous processes (C5 and C6) were exposed. A 16-mm tubular retractor was inserted between the tips of the C5 and C6 spinous processes. A dome-like laminectomy of C5, partial laminectomy of the upper part of C6, and flavectomy were performed. For the two-level cases (e.g., C4-C5 and C5-C6), the decompression procedure was completed by splitting the spinous process (C5). Pre- and postoperative neurologic status was evaluated using the Japanese Orthopedic Association (JOA) score. Neck and arm pain was also evaluated using a numerical rating scale (NRS). Results Overall, 10 patients underwent single-level decompression, and 19 patients underwent two-level decompression. The average age was 67 years (range: 40-83 years), and the mean follow-up period was 11 months (range: 4-14 months). The average pre- and postoperative JOA scores were 10.2 and 13.5, with a mean recovery rate of 49%. The mean preoperative and postoperative NRS scores were 3.5 and 1.5 for neck pain and 4.6 and 2.9 for arm pain, respectively. One patient showed transient mild weakness of the leg that recovered neurologically within a few weeks. No other postoperative complications were observed. Conclusion This procedure revealed good short-term surgical results. This technique has advantages including (1) a symmetrical orientation of the surgical field, (2) an intermuscular incision that minimizes blood loss and muscle trauma, and (3) the ability to safely complete the decompression procedure without retracting the cervical spinal cord compared with the unilateral approach. Although long-term surgical results are required, this technique is not only safe but also minimally invasive as a treatment for cervical compression myelopathy.
    Journal of neurological surgery. Part A, Central European neurosurgery. 05/2014;
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    ABSTRACT: There have been no nationwide surveys of postoperative adverse events (AEs) after musculoskeletal tumor surgery focusing on their severity. Therefore, we developed a nomogram to predict severe AEs after musculoskeletal tumor surgery. We identified patients in the Diagnosis Procedure Combination database who underwent musculoskeletal tumor surgery during 2007-2012, and defined severe AEs as follows: (i) in-hospital mortality; (ii) postoperative medications including massive transfusion (≥1,400 mL), catecholamines, γ-globulin products, protease inhibitors, and medications for disseminated intravascular coagulation; and (iii) postoperative interventions consisting of mechanical ventilation, dialysis support, and cardiac support. Logistic regression models were used to address the occurrence of severe AEs. Of 5,716 patients identified, 613 patients (10.7 %) had severe AEs. Multivariate analyses showed an inverse relationship between body mass index (BMI) and severe AEs (odds ratio 1.80 for BMI <18.50; p < 0.001) after adjustment for other significant factors, including sex, age, tumor location, Charlson comorbidity index, type of surgery, and duration of anesthesia. A nomogram and a calibration plot based on these results were well-fitted to predict the probability of severe AEs after musculoskeletal tumor surgery (concordance index 0.781). We developed a nomogram predicting the probability of severe AEs after musculoskeletal tumor surgery. In addition, we clarified that underweight, but not overweight or obese, status was significantly associated with increased severe AEs after adjusting for patient background characteristics.
    Annals of Surgical Oncology 05/2014; · 4.12 Impact Factor
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    ABSTRACT: We aimed to assess the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) and its association with lumbar spondylosis (LS) and knee osteoarthritis (KOA) using a population-based cohort study entitled Research on Osteoarthritis/osteoporosis Against Disability (ROAD). In the baseline ROAD study, which was performed between 2005 and 2007, 1,690 participants in mountainous and coastal areas underwent anthropometric measurements and radiographic examinations of the whole spine (cervical, thoracic, and lumbar) and both knees. They also completed an interviewer-administered questionnaire. Presence of DISH was diagnosed according to Resnick criteria, and LS and KOA were defined as Kellgren-Lawrence (KL) grade ≥3. Among the 1,690 participants, whole-spine radiographs of 1,647 individuals (97.5 %; 573 men, 1,074 women; mean age, 65.3 years) were evaluated. Prevalence of DISH was 10.8 % (men 22.0 %, women 4.8 %), and was significantly higher in older participants (presence of DISH 72.3 years, absence of DISH 64.4 years) and mainly distributed at the thoracic spine (88.7 %). Logistic regression analysis revealed that presence of DISH was significantly associated with older age [+1 year, odds ratio (OR): 1.06, 95 % confidence interval (CI): 1.03-1.14], male sex (OR: 5.55, 95 % CI: 3.57-8.63), higher body mass index (+1 kg/m(2), OR: 1.08, 95 % CI: 1.02-1.14), presence of LS (KL2 vs KL0: 1, OR: 5.50, 95 % CI: 2.81-10.8) (KL ≥3 vs KL0: 1, OR: 4.09, 95 % CI: 2.08-8.03), and presence of KOA (KL ≥3 vs KL0: 1, OR: 1.89, 95 % CI: 1.14-3.10) after adjusting for smoking, alcohol consumption, and residential area (mountainous vs coastal). This cross-sectional population-based study clarified the prevalence of DISH in general inhabitants and its significant association with LS and severe KOA.
    Journal of Bone and Mineral Metabolism 03/2014; · 2.22 Impact Factor
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    ABSTRACT: Objectives. To examine the onset and resolution of pain and physical functional disability using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and their association with knee osteoarthritis (OA) in the longitudinal large-scale population of the nationwide cohort study, Research on Osteoarthritis/osteoporosis Against Disability (ROAD). Methods. Subjects from the ROAD study who had been recruited during 2005-2007 were followed up 3 years later. A total of 1,578 subjects completed the WOMAC questionnaire at baseline and follow up, and the onset and resolution rate of pain and physical functional disability were examined. We also examined the association of onset of pain and physical functional disability and their resolution with severity of knee OA as well as age, body-mass index and grip strength. Results. After a 3.3-year follow-up, the onset rate of pain was 35.0% and 35.3% in men and women, respectively, and the onset rate of physical functional disability was 38% and 40%, respectively. Resolution rate of pain was 20.3% and 26.2% in men and women, respectively, and resolution rate of physical functional disability was 16% and 14% in men and women, respectively. Knee OA was significantly associated with onset and resolution of pain and physical functional disability in women, but there was no significant association of knee OA with onset of pain and resolution of physical functional disability in men. Conclusions. The present longitudinal study revealed the onset rate of pain and physical functional disability as well as their resolution, and their association with knee OA.
    Modern Rheumatology 03/2014; · 1.72 Impact Factor
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    ABSTRACT: The present study aimed to investigate association of physical activities of daily living with the incidence of certified need of care in the national long-term care insurance (LTCI) system in elderly Japanese population-based cohorts. Of the 3,040 participants in the baseline examination, we enrolled 1,773 (699 men, 1,074 women) aged 65 years or older who were not certified as in need of care-level elderly at baseline. Participants were followed during an average of 4.0 years for incident certification of need of care in the LTCI system. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used assess function. Associated factors in the baseline examination with the occurrence were determined by multivariate Cox proportional hazards regression analysis. Receiver operating characteristic curve analysis was performed to evaluate cut-off values for discriminating between the occurrence and the non-occurrence group. All 17 items in the WOMAC function domain were significantly associated with the occurrence of certified need of care in the overall population. Cut-off values of the WOMAC function score that maximized the sum of sensitivity and specificity were around 4-6 in the overall population, in men, and in women. Multivariate Cox hazards regression analysis revealed that a WOMAC function score ≥4 was significantly associated with occurrence with the highest hazard ratio (HR) for occurrence after adjusting for confounders in the overall population (HR [95 % confidence interval (CI)] 2.54 [1.76-3.67]) and in women [HR (95 % CI) 3.13 (1.95-5.02)]. A WOMAC function score ≥5 was significantly associated with the highest HR for occurrence in men [HR (95 % CI) 1.88 (1.03-3.43)]. Physical dysfunction in daily living is a predictor of the occurrence of certified need of care. Elderly men with a WOMAC function score ≥5 and women with a score ≥4 should undergo early intervention programs to prevent subsequent deterioration.
    Journal of Orthopaedic Science 02/2014; · 0.96 Impact Factor
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    ABSTRACT: The incidence and relevant risk of ischemic stroke following cervical spine trauma remain unknown. To examine the incidence of ischemic stroke during hospitalization in patients with cervical spine injury and analyze the impact of different types of cervical spine injury on the occurrence of ischemic stroke. Study Design/Setting: Retrospective analysis of data abstracted from the Diagnosis Procedure Combination database, a nationally representative database in Japan. We included all patients hospitalized for any of the following traumas: fracture of cervical spine (International Classification of Diseases, 10th Revision codes: S120, S121, S122, S127, S129); dislocation of cervical spine (S131, S133); cervical spinal cord injury (S141). Outcome measures included all-cause in-hospital mortality and incidence of ischemic stroke (I63) during hospitalization. We analyzed the effects of age, sex, comorbidities, smoking status, spinal surgery, consciousness level at admission, and type of cervical spine injury on outcomes. This study was funded by a research grant from the Ministry of Health, Labour, and Welfare and the Council for Science and Technology Policy. There were no potential conflicts of interest to disclose. We identified 11,005 patients with cervical spine injury (8,031 men, 2,974 women; mean [standard deviation] age, 63.5 [18] years). According to the types of cervical spine injury, we stratified the patients into three groups: 1) cervical fracture and/or dislocation without spinal cord injury (SCI) (2,363 patients); 2) cervical fracture and/or dislocation associated with SCI (1,283 patients); and 3) cervical SCI without fracture and/or dislocation (7,359 patients). Overall, ischemic stroke occurred in 115 (1.0%) patients during hospitalization (median length of stay, 26 days). In-hospital death occurred in 456 (4.1%) patients. Multivariate analyses showed that ischemic stroke after cervical spine injury was significantly associated with age, diabetes, and consciousness level at admission. The highest in-hospital mortality was observed in patients with cervical fracture and/or dislocation associated with SCI (7.6%), followed by cervical SCI without fracture and/or dislocation (4.0%), and cervical fracture and/or dislocation without SCI (2.6%). Unlike mortality, risks of stroke did not vary significantly among the three groups. This analysis revealed that ischemic stroke following cervical spine injury was not uncommon and was associated with increased mortality and morbidity. Occurrence of ischemic stroke was significantly associated with age, comorbidities such as diabetes, and consciousness level at admission, but not with type of spine injury.
    The spine journal: official journal of the North American Spine Society 01/2014; · 2.90 Impact Factor
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    ABSTRACT: Clumsiness and numbness of the upper extremity is one of the most common complaints of patients with cervical myelopathy. However, most previous evaluations after cervical laminoplasty have only been based on physicians' points of view. We used Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) self-report questionnaire, which was designed to measure physical function and symptoms in people with upper-limb disorders to evaluate functional outcomes after laminoplasty. Ninety-four patients who underwent laminoplasty for cervical myelopathy and replied to the questionnaire were included in this study. The average age was 62 years, and mean follow-up period was 61 months. The Japanese Orthopedic Association (JOA) score, Neck Disability Index (NDI), Short-Form Health Questionnaire of 36 questions (physical component score, PCS), upper-extremity pain (Numerical Rating Scale), and QuickDASH (0-100, 0 being least severe) were used to evaluate surgical outcomes. Satisfaction with treatment was also investigated, and internal consistency and criterion-related validity were evaluated. The QuickDASH cutoff value for patient satisfaction was determined by receiver operating characteristic curve (ROC) analysis. The mean total JOA scores were 10 before and 13 after surgery, and average postoperative QuickDASH score was 30. Cronbach α of the QuickDASH was 0.94. QuickDASH was significantly correlated with JOA score for upper-extremity motor and sensation, NDI, PCS, and pain. Cutoff value of the QuickDASH was 34.0 by ROC analysis. Significantly better QuickDASH scores were found for patients who were satisfied with treatment than for those who were not, whereas JOA score for upper-extremity motor function did not show a significant difference. QuickDASH had significant correlations with disease-specific JOA scores and other generic outcome measures. Moreover, QuickDASH significantly reflected patients' satisfaction with treatment, whereas the JOA score for upper-extremity motor function did not. QuickDASH was useful in evaluating upper-extremity functional outcomes after cervical laminoplasty.
    Journal of Orthopaedic Science 01/2014; · 0.96 Impact Factor
  • Naoto Tokuyama, Sakae Tanaka
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    ABSTRACT: Osteoporosis and osteoporosis-related fractures tend to increase year by year around the world including Japan. Denosumab, a fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL) , a cytokine member of the TNF family essential for osteoclast differentiation has recently been approved in Japan, Europe and the US for the treatment of postomenopausal osteoporosis as well as bone metastasis. In some large clinical trials, denosumab significantly decreased bone resorption, increased bone mineral density (BMD) , and reduced the risk of vertebral, nonvertebral and hip fractures in postmenopausal women. However, the mechanism of adverse events of denosumab, such as hypocalcemia and osteonecrosis of the jaws, has not been completely explained. Therefore, further knowledge should be accumulated by additional basic researches and clinical studies on denosumab.
    Clinical calcium 01/2014; 24(1):85-91.
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    ABSTRACT: Purpose The purpose of this study was to retrospectively evaluate femoral tunnel widening (TW) and migration of the femoral tunnel aperture after anatomic anterior cruciate ligament (ACL) reconstructions with hamstring grafts and bone–patellar tendon–bone (BPTB) grafts. Methods Of the 105 consecutive patients who underwent ACL reconstruction, the 52 patients who underwent isolated ACL reconstruction and in whom tunnel measurement could be obtained by computed tomography were included in this study. In 26 patients, double-bundle reconstruction (DBR) of the ACL using hamstring tendons was performed. These patients were compared with 26 patients in whom rectangular tunnel ACL reconstruction using BPTB grafts (BPTBR) was performed. Femoral tunnel aperture positioning and TW were investigated postoperatively using 3-dimensional computed tomographic images, which were performed a week and a year after surgery in all patients. Results In DBR, the average diameter of the anteromedial (AM) femoral tunnel increased by 34.0% in the horizontal direction and 28.2% in the vertical direction, whereas that of the posterolateral (PL) femoral tunnel increased by 58.2% and 73.4%, respectively, at 1 year after surgery compared with 1 week after surgery. The percentage TW value of the PL tunnel was significantly greater than that of the AM tunnel. In BPTBR, the average diameter increased by 22.0% and 17.1%, respectively. The percentage TW value of the PL tunnel in DBR was significantly greater than that of the femoral tunnel in BPTBR. Each tunnel aperture migrated distally (“shallow”) in the horizontal direction and high in the vertical direction. AM and PL tunnel apertures in DBR migrated in the vertical direction significantly more than they did in BPTBR. No significant differences between the 2 groups were found in clinical outcomes. Conclusions The femoral PL tunnel aperture in DBR showed significantly more widening than did the AM tunnel aperture in DBR and the femoral tunnel aperture in BPTBR. Also, greater migration of the femoral tunnel aperture in the vertical direction because of TW was observed in DBR than in BPTBR. Level of Evidence Level IV, therapeutic case series.
    Arthroscopy The Journal of Arthroscopic and Related Surgery 01/2014; · 3.10 Impact Factor
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    ABSTRACT: Osteoporosis is an age-related systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility. Bone remodeling involves two types of cells: osteoblasts and osteoclasts. Receptor activator of nuclear factor-κB ligand (RANKL) is a key regulator of the formation and function of bone-resorbing osteoclasts, and its cell surface receptor, receptor activator of nuclear factor-κB (RANK), is expressed by both osteoclast precursors and mature osteoclasts. Denosumab is a fully human monoclonal anti-RANKL antibody that inhibits the binding of RANKL to RANK, thereby decreasing osteoclastogenesis and bone-resorbing activity of mature osteoclasts. Although there are many medications available for the treatment of osteoporosis, inhibition of RANKL by denosumab has been shown to significantly affect bone metabolism. Denosumab appears to be a promising, highly effective, and safe parenteral therapy with good adherence for osteoporosis. Moreover, denosumab may be cost-effective therapy compared with existing alternatives. Therefore, in this review, we focus on studies of denosumab and the risks and benefits identified for this type of treatment for osteoporosis.
    Patient Preference and Adherence 01/2014; 8:463-471. · 1.33 Impact Factor
  • Hiroshi Kobayashi, Taku Saito, Sakae Tanaka
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    ABSTRACT: Endochondral ossification is an essential process for skeletal development, in which chondrocyte undergoes apoptosis and induces mineralization after terminal differentiation. The apoptosis of chondrocyte is accompanied by marked accumulation of extracellular phosphate ions, which up-regulates the concentration of intra-cellular phosphate ions and leads to the activation of pro-apoptotic factors. The mineralization of chondrocyte is regulated by the orchestrated process mediated by intra-vesicular phosphate ion production by PHOSPHO1, phosphate ion influx into matrix vesicles through Pit-1, and the functions of TNAP and NPP1 that controls pyrophosphate to phosphate ratio in the extra-vesicular progression of mineralization. The apoptosis and mineralization of chondrocyte are related to not only skeletal development but also pathological conditions such as rickets/osteomalacia and osteoarthritis.
    Clinical calcium 01/2014; 24(2):177-84.
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    ABSTRACT: Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal-related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
    Journal of Experimental Medicine 12/2013; · 13.21 Impact Factor
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    ABSTRACT: Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic TH17 cells in autoimmunity.
    Nature medicine 12/2013; · 27.14 Impact Factor
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    ABSTRACT: Functional disability is a major concern in patients with rheumatoid arthritis (RA). This retrospective study investigated the risk factors for vertebral fractures (VFs) in postmenopausal RA patients and determined the impact of VFs on functional status. Data from a cohort of 200 postmenopausal RA patients in a single hospital registry were analyzed. Demographic and clinical data, imaging data from spine radiographs, and bone mineral density (BMD) data were collected from the patients at baseline and at the final visit (a mean of 2.9 years after the first visit). Risk factors for incident VFs and their impact on the modified health assessment questionnaire (mHAQ) were analyzed. Twenty-eight patients (14 %) developed new VFs (NVFs). Logistic regression analysis adjusted for age, BMI, and disease duration revealed that daily dose of prednisolone, femoral neck BMD, use of active vitamin D3, and use of a bisphosphonate at baseline were factors associated with NVF, with odds ratios (95 % confidence interval) of 1.27 (1.05-1.54), 0.94 (0.91-0.97), 0.34 (0.13-0.89), and 0.31 (0.12-0.82), respectively. Patients with NVF exhibited worse mHAQ scores and a greater increase in mHAQ scores from baseline compared with those without NVF. In conclusion, incident VFs were associated with reduced functional status in postmenopausal patients with RA. It is important to prevent VFs to maintain the functional status of RA patients.
    Journal of Bone and Mineral Metabolism 12/2013; · 2.22 Impact Factor
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    ABSTRACT: We investigated the midterm results of resection arthroplasty of all 5 metatarsal heads in patients with rheumatoid arthritis and forefoot deformity and analyzed the factors that affect patient satisfaction levels. Of 64 patients (1 male, 63 females), 107 feet were treated with resection arthroplasty for forefoot deformity at our hospital from January 1992 to December 2005. The mean follow-up period was 5.8 ± 3.1 years, with all patients having at least 1 year of follow-up. Of the 64 patients, 75% were satisfied with the surgery. The mean score for the postoperative Japanese Society for Surgery of the Foot lesser metatarsophalangeal-interphalangeal scale was 75.0 ± 15.8 points. Multivariate logistic regression analysis showed that patient-reported dissatisfaction was significantly associated with the recurrence of hammer toe deformity (odds ratio 2.66, 95% confidence interval 1.07 to 6.97), shortening of the resection arthroplasty space (odds ratio 0.85 for a 1-unit increase, 95% confidence interval 0.74 to 0.96), and the recurrence of hallux valgus (odds ratio 1.04 for a 1-unit increase, 95% confidence interval 1.00 to 1.09) during the postoperative period. From our results, interventions to prevent recurrence of hammer toe deformity, especially in toes with preoperative metatarsophalangeal joint dislocations, have been shown to be important in preventing complications and patient dissatisfaction after resection arthroplasty.
    The Journal of foot and ankle surgery: official publication of the American College of Foot and Ankle Surgeons 11/2013;

Publication Stats

4k Citations
546.62 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
  • 1993
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan