Updated on 2022/05/12

写真a

 
TERABE Kenya
 
Organization
Nagoya University Hospital Orthopedics Assistant professor of hospital
Title
Assistant professor of hospital

Degree 1

  1. 医学博士 ( 2016.10   名古屋大学 ) 

Research Areas 1

  1. Life Science / Orthopedics

Awards 1

  1. 第26回軟骨代謝学会賞

    2021.3   軟骨代謝学会  

    寺部健哉

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    Award type:Award from Japanese society, conference, symposium, etc. 

 

Papers 36

  1. Effectiveness of tacrolimus concomitant with biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis Reviewed

    Terabe Kenya, Takahashi Nobunori, Asai Shuji, Hirano Yuji, Kanayama Yasuhide, Yabe Yuichiro, Oguchi Takeshi, Fujibayashi Takayoshi, Ishikawa Hisato, Hanabayashi Masahiro, Hattori Yosuke, Suzuki Mochihito, Kishimoto Kenji, Ohashi Yoshifumi, Imaizumi Takahiro, Imagama Shiro, Kojima Toshihisa

    MODERN RHEUMATOLOGY     2022.3

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    Authorship:Lead author   Language:English  

    DOI: 10.1093/mr/roac025

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  2. Metabolic changes in synovial cells in early inflammation: Involvement of CREB phosphorylation in the anti-inflammatory effect of 2-deoxyglucose Reviewed

    Kishimoto Kenji, Terabe Kenya, Takahashi Nobunori, Yokota Yutaka, Ohashi Yoshifumi, Hattori Kyosuke, Kihira Daisuke, Maeda Masataka, Kojima Toshihisa, Imagama Shiro

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 708   page: 108962   2021.9

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    Authorship:Corresponding author   Language:English  

    DOI: 10.1016/j.abb.2021.108962

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  3. Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis Reviewed

    Ohashi Yoshifumi, Takahashi Nobunori, Terabe Kenya, Tsuchiya Saho, Kojima Toshihisa, Knudson Cheryl B., Knudson Warren, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 15131   2021.7

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    Authorship:Corresponding author   Language:English  

    DOI: 10.1038/s41598-021-94611-9

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  4. Influence of frailty on patient global assessment in rheumatoid arthritis Reviewed

    Suzuki Mochihito, Asai Shuji, Sobue Yasumori, Ohashi Yoshifumi, Koshima Hiroshi, Okui Nobuyuki, Ishikawa Hisato, Takahashi Nobunori, Terabe Kenya, Kishimoto Kenji, Hattori Kyosuke, Imagama Shiro, Kojima Toshihisa

    GERIATRICS & GERONTOLOGY INTERNATIONAL   Vol. 22 ( 5 ) page: 399 - 404   2022.5

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  5. Factors associated with frailty in rheumatoid arthritis patients with decreased renal function Reviewed

    Ohashi Yoshifumi, Takahashi Nobunori, Sobue Yasumori, Suzuki Mochihito, Hattori Kyosuke, Kishimoto Kenji, Terabe Kenya, Asai Syuji, Kojima Toshihisa, Kojima Masayo, Imagama Shiro

    MODERN RHEUMATOLOGY     2022.4

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  6. Relationship between locomotive syndrome and frailty in rheumatoid arthritis patients by locomotive syndrome stage Reviewed

    Sobue Yasumori, Suzuki Mochihito, Ohashi Yoshifumi, Koshima Hiroshi, Okui Nobuyuki, Funahashi Koji, Ishikawa Hisato, Asai Shuji, Terabe Kenya, Yokota Yutaka, Kishimoto Kenji, Takahashi Nobunori, Imagama Shiro, Kojima Toshihisa

    MODERN RHEUMATOLOGY   Vol. 32 ( 3 ) page: 546 - 553   2022.4

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  7. The Efficacy and Safety of a Novel Extramedullary Guide Coordinated with 3D Surgical Assistive Software for Total Knee Arthroplasty: an Open-Label Single-Arm Trial Reviewed

    KIDA DAIHEI, HASHIMOTO HIROYA, SAITO AKIKO M., KITO YUKARI, HATTORI YOSUKE, TERABE KENYA, MORI KOUICHI, TAKAHASHI NOBUNORI, TOMITA YASUSHI

    The Kurume Medical Journal   Vol. 67 ( 1 ) page: 31 - 40   2022.3

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    Language:English   Publisher:Kurume University School of Medicine  

    <p><b>Summary:</b><i><b> </b></i>To improve component-placement accuracy in total knee arthroplasty, we developed two devices: an original extramedullary patient-specific guide for the femur and an original extramedullary universal guide for the tibia (EM-TIBIA). We also developed a new function in ZedView, a three-dimensional surgical assistive software, that provides the parameters necessary to install the EM-TIBIA. Compared with conventional manual methods based on X-ray two-dimensional images or ZedView, these newly developed devices function as an extramedullary intraoperative support guide in conjunction with ZedView, simplifying surgical procedures. We conducted a study to evaluate the efficacy and safety of the surgery using the new guides and software function. Nineteen patients underwent surgery. On the femoral side, the mean absolute difference of the installation alignment was within 3° for all parameters. On the other hand, on the tibial side, the mean absolute difference from the preoperative plan for the rotation was 5.26±5.30°. The proportion of patients whose difference fell within ±3° was 52.6% (95% confi dence interval: 28.9 to 75.6%), and did not meet the pre-specified criteria for efficacy (P=0.261). No serious adverse events were reported, and no excessive bleeding, thrombosis, infections, or intraoperative or postoperative fractures were noted. The two new guides can easily reproduce the preoperative plan as 3D intraoperative support jigs, but errors can occur on the tibia side due to soft tissue that is not recognized by CT, creating problems in installation accuracy.</p>

    DOI: 10.2739/kurumemedj.MS671002

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  8. Comparison of the effects of baricitinib and tocilizumab on disease activity in patients with rheumatoid arthritis: a propensity score matching analysis Reviewed

    Asai Shuji, Takahashi Nobunori, Kobayakawa Tomonori, Kaneko Atsushi, Watanabe Tatsuo, Kato Takefumi, Nishiume Tsuyoshi, Ishikawa Hisato, Yoshioka Yutaka, Kanayama Yasuhide, Watanabe Tsuyoshi, Hirano Yuji, Hanabayashi Masahiro, Yabe Yuichiro, Yokota Yutaka, Suzuki Mochihito, Terabe Kenya, Ishiguro Naoki, Imagama Shiro, Kojima Toshihisa

    CLINICAL RHEUMATOLOGY   Vol. 40 ( 8 ) page: 3143 - 3151   2021.8

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  9. Activation of transient receptor potential vanilloid 4 protects articular cartilage against inflammatory responses via CaMKK/AMPK/NF-kappa B signaling pathway Reviewed

    Hattori Kyosuke, Takahashi Nobunori, Terabe Kenya, Ohashi Yoshifumi, Kishimoto Kenji, Yokota Yutaka, Suzuki Mochihito, Kojima Toshihisa, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 15508   2021.7

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  10. Higher doses of methotrexate associated with discontinuation of oral glucocorticoids after initiation of biological DMARDs: A retrospective observational study based on data from a Japanese multicenter registry study Reviewed

    Suzuki Mochihito, Kojima Toshihisa, Takahashi Nobunori, Asai Shuji, Terabe Kenya, Kaneko Atsushi, Hirano Yuji, Hanabayashi Masahiro, Oguchi Takeshi, Takagi Hideki, Kanayama Yasuhide, Yabe Yuichiro, Funahashi Koji, Fujibayashi Takayoshi, Tsuboi Seiji, Ito Takayasu, Yoshioka Yutaka, Ishikawa Hisato, Sobue Yasumori, Nishiume Tsuyoshi, Yokota Yutaka, Ishiguro Naoki

    MODERN RHEUMATOLOGY   Vol. 31 ( 4 ) page: 796 - 802   2021.7

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1080/14397595.2021.1879428

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  11. Relationship between disease activity of rheumatoid arthritis and development of locomotive syndrome: A five-year longitudinal cohort study Reviewed

    Sobue Yasumori, Kojima Toshihisa, Funahashi Koji, Okui Nobuyuki, Takahashi Nobunori, Asai Shuji, Terabe Kenya, Nishiume Tsuyoshi, Suzuki Mochihito, Yokota Yutaka, Ohashi Yoshifumi, Ishiguro Naoki

    MODERN RHEUMATOLOGY   Vol. 31 ( 1 ) page: 101 - 107   2021.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Modern Rheumatology  

    Objective: This study aimed to longitudinally evaluate the association between rheumatoid arthritis (RA) and locomotive syndrome (LS) in RA patients using the 25-question Geriatric Locomotive Function Scale (GLFS-25). Methods: Subjects were 58 RA patients (female, 48 (82.8%); mean age, 60.9 ± 10.9 years) who had GLFS-25 scores available for five consecutive years and who did not have LS at baseline (i.e. GLFS-25 < 16 points). Associations between DAS28-CRP and the development of LS were determined using linear regression analysis and receiver operating characteristic (ROC) curve analysis. Results: Subjects were divided into the LS group (n = 15, GLFS-25 ≥ 16 points) and non-LS group (n = 43, GLFS-25 < 16 points) based on GLFS-25 scores at the 5th year of the study period. In the LS group, DAS28-CRP worsened every year. The linear regression model adjusted for age and sex revealed that ΔGLFS-25 increased by 3.80 (95% confidence interval: 1.81–5.79) each time ΔDAS28-CRP increased by 1 (p<.001). Among patients in remission (DAS28-CRP < 2.3), 13.5% had LS. ROC curve analysis yielded a five-year mean DAS28-CRP of 1.99 (sensitivity, 86.7%; specificity, 62.8%) as the cut-off point for the development of LS. Conclusion: Tight control of RA disease activity for deeper remission may be needed to prevent the development of LS.

    DOI: 10.1080/14397595.2020.1744828

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  12. Predictors for clinical effectiveness of baricitinib in rheumatoid arthritis patients in routine clinical practice: data from a Japanese multicenter registry Reviewed

    Takahashi Nobunori, Asai Shuji, Kobayakawa Tomonori, Kaneko Atsushi, Watanabe Tatsuo, Kato Takefumi, Nishiume Tsuyoshi, Ishikawa Hisato, Yoshioka Yutaka, Kanayama Yasuhide, Watanabe Tsuyoshi, Hirano Yuji, Hanabayashi Masahiro, Yabe Yuichiro, Yokota Yutaka, Suzuki Mochihito, Sobue Yasumori, Terabe Kenya, Ishiguro Naoki, Kojima Toshihisa

    SCIENTIFIC REPORTS   Vol. 10 ( 1 ) page: 21907   2020.12

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Scientific Reports  

    This study aimed to evaluate the short-term effectiveness and safety profiles of baricitinib and explore factors associated with improved short-term effectiveness in patients with rheumatoid arthritis (RA) in clinical settings. A total of 113 consecutive RA patients who had been treated with baricitinib were registered in a Japanese multicenter registry and followed for at least 24 weeks. Mean age was 66.1 years, mean RA disease duration was 14.0 years, 71.1% had a history of use of biologics or JAK inhibitors (targeted DMARDs), and 48.3% and 40.0% were receiving concomitant methotrexate and oral prednisone, respectively. Mean DAS28-CRP significantly decreased from 3.55 at baseline to 2.32 at 24 weeks. At 24 weeks, 68.2% and 64.1% of patients achieved low disease activity (LDA) and moderate or good response, respectively. Multivariate logistic regression analysis revealed that no previous targeted DMARD use and lower DAS28-CRP score at baseline were independently associated with achievement of LDA at 24 weeks. While the effectiveness of baricitinib was similar regardless of whether patients had a history of only one or multiple targeted DMARDs use, patients with previous use of non-TNF inhibitors or JAK inhibitors showed lower rates of improvement in DAS28-CRP. The overall retention rate for baricitinib was 86.5% at 24 weeks, as estimated by Kaplan–Meier analysis. The discontinuation rate due to adverse events was 6.5% at 24 weeks. Baricitinib significantly improved RA disease activity in clinical practice. Baricitinib was significantly more effective when used as a first-line targeted DMARDs.

    DOI: 10.1038/s41598-020-78925-8

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  13. A retrospective analysis of the relationship between anti-cyclic citrullinated peptide antibody and the effectiveness of abatacept in rheumatoid arthritis patients Reviewed

    Kida Daihei, Takahashi Nobunori, Kaneko Atsushi, Hirano Yuji, Fujibayashi Takayoshi, Kanayama Yasuhide, Hanabayashi Masahiro, Yabe Yuichiro, Takagi Hideki, Oguchi Takeshi, Kato Takefumi, Funahashi Koji, Matsumoto Takuya, Ando Masahiko, Kuwatsuka Yachiyo, Tanaka Eiichi, Yasuoka Hidekata, Kaneko Yuko, Hirata Shintaro, Murakami Kosaku, Sobue Yasumori, Nishiume Tsuyoshi, Suzuki Mochihito, Yokota Yutaka, Terabe Kenya, Asai Shuji, Ishiguro Naoki, Kojima Toshihisa

    SCIENTIFIC REPORTS   Vol. 10 ( 1 ) page: 19717   2020.11

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    This study aimed to evaluate the effectiveness of abatacept (ABA) by anti-cyclic citrullinated peptide (ACPA) status on disease activity as well as radiographic progression in patients with rheumatoid arthritis (RA) in clinical settings. A retrospective cohort study was conducted using data from a multicenter registry. Data from a total of 553 consecutive RA patients treated with intravenous ABA were included. We primarily compared the status of disease activity (SDAI) and radiographic progression (van der Heijde modified total Sharp score: mTSS) between the ACPA-negative (N = 107) and ACPA-positive (N = 446) groups. ‘ACPA positive’ was defined as ≥ 13.5 U/mL of anti-CCP antibody. Baseline characteristics between groups were similar. The proportion of patients who achieved low disease activity (LDA; SDAI ≤ 11) at 52 weeks was significantly higher in the ACPA-positive group. Multivariate logistic regression analysis identified ACPA positivity as an independent predictor for achievement of LDA at 52 weeks. Drug retention rate at 52 weeks estimated by the Kaplan–Meier curve was significantly higher in the ACPA-positive group. Achievement rate of structural remission (ΔmTSS ≤ 0.5) at 52 weeks was similar between groups. ABA treatment demonstrated a significantly higher clinical response and higher drug retention rate in ACPA-positive patients. Progression of joint destruction was similar between the ACPA-negative and ACPA-positive groups. Close attention should be paid to joint destruction even in patients showing a favorable response to ABA, especially when the ACPA status is positive.

    DOI: 10.1038/s41598-020-76842-4

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  14. Periarticular osteophyte formation protects against total knee arthroplasty in rheumatoid arthritis patients with advanced joint damage

    Asai Shuji, Takahashi Nobunori, Terabe Kenya, Sobue Yasumori, Nishiume Tsuyoshi, Suzuki Mochihito, Yokota Yutaka, Ishiguro Naoki, Kojima Toshihisa

    CLINICAL RHEUMATOLOGY   Vol. 39 ( 11 ) page: 3331 - 3339   2020.11

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    Language:Japanese   Publisher:Clinical Rheumatology  

    Objective: Periarticular osteophyte formation is observed during the repair of damaged joints in rheumatoid arthritis (RA); however, little is known about its clinical and functional roles. This study aimed to determine the influence of periarticular osteophyte formation on the incidence of total knee arthroplasty (TKA) (a surrogate for long-term outcomes of joint destruction) in patients with RA. Methods: This retrospective longitudinal study included a total of 130 symptomatic (tender and/or swollen) knee joints in 80 patients starting biologics. Cumulative incidences of TKA were compared according to the presence or absence of osteophyte on plain anteroposterior radiograph (osteophyte (±)) and the extent of advanced joint damage as defined by Larsen’s grading system (0–II vs. III–V). Results: Kaplan-Meier estimates showed a significantly lower cumulative incidence of TKA for the osteophyte (+) group (n = 33) compared with the osteophyte (−) group (n = 31) in the Larsen grades III–V group (38 vs. 74% at 10 years, P = 0.010), whereas no significant difference was observed between the osteophyte (+) (n = 11) and osteophyte (−) (n = 55) groups in the Larsen grades 0–II group (9 vs. 10% at 10 years). Multivariate Cox proportional hazards analysis revealed that older age (hazard ratio (HR), 1.04 per 1 year; 95% confidence interval (CI), 1.01–1.08) and osteophyte formation (HR, 0.39; 95% CI, 0.19–0.79) independently predicted TKA in the Larsen grades III–V group, whereas none of the assessed variables predicted TKA in the Larsen grades 0–II group. Conclusion: Osteophyte formation reduces the incidence of TKA in patients with RA who have advanced joint damage.Key Points• Older age and Larsen grade were independent predictors of total knee arthroplasty (TKA) in rheumatoid arthritis (RA) patients.• Periarticular osteophyte formation reduced the incidence of TKA in RA patients with Larsen grades III–V.

    DOI: 10.1007/s10067-020-05140-1

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  15. Improvement in matrix metalloproteinase-3 independently predicts low disease activity at 52 weeks in bio-switch rheumatoid arthritis patients treated with abatacept Reviewed

    Takemoto T., Takahashi N., Kida D., Kaneko A., Hirano Y., Fujibayashi T., Kanayama Y., Hanabayashi M., Yabe Y., Takagi H., Oguchi T., Kato T., Funahashi K., Matsumoto T., Sobue Y., Nishiume T., Suzuki M., Yokota Y., Terabe K., Asai S., Ishiguro N., Kojima T.

    Clinical and Experimental Rheumatology   Vol. 38 ( 5 ) page: 933 - 939   2020.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Clinical and Experimental Rheumatology  

    Objective To explore predictive factors including MMP-3 for achievement of low disease activity (LDA) at 52 weeks in bio-switch rheumatoid arthritis (RA) patients treated with abatacept, for whom obtaining a good clinical response can be difficult. Methods Participants were 423 consecutive patients with RA treated with abatacept who were observed for longer than 52 weeks and registered in the TBCR, a Japanese multicentre registry system. Multivariate logistic regression analysis was used to study factors that predict the achievement of LDA at 52 weeks in bio-naïve (n=234) and bio-switch (n=189) groups. Results ROC analysis revealed that MMP-3 improvement rates at 12 weeks in bio-switch patients had the highest AUC with a cut-off value of 20.0% for predicting LDA achievement at 52 weeks. Multivariate logistic regression analysis revealed that, in addition to DAS28-CRP at baseline, achieving 20% improvement in MMP-3 levels at 12 weeks was an independent predictive factor (adjusted OR: 4.277, p=0.003) in the bio-switch group, whereas DAS28 was the only predictor in the bio-naïve group. Patients who achieved 20% improvement in MMP-3 levels at 12 weeks had significantly higher achievement rates of LDA at 52 weeks compared to those who did not achieve 20% improvement in the bio-switch group (60.0 vs. 33.3%, p=0.001). Conclusions Our findings suggest that improvement in MMP-3 levels is key to predicting the clinical efficacy of abatacept. Closer attention paid not only to major clinical indices, but also changes in MMP-3 levels, could improve our ability to optimise clinical results when treating bio-switch patients.

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  16. Improvement in matrix metalloproteinase-3 independently predicts low disease activity at 52 weeks in bio-switch rheumatoid arthritis patients treated with abatacept.

    Takemoto T, Takahashi N, Kida D, Kaneko A, Hirano Y, Fujibayashi T, Kanayama Y, Hanabayashi M, Yabe Y, Takagi H, Oguchi T, Kato T, Funahashi K, Matsumoto T, Sobue Y, Nishiume T, Suzuki M, Yokota Y, Terabe K, Asai S, Ishiguro N, Kojima T

    Clinical and experimental rheumatology   Vol. 38 ( 5 ) page: 933 - 939   2020.9

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  17. Characteristics of patients with rheumatoid arthritis undergoing primary total joint replacement: A 14-year trend analysis (2004-2017)

    Asai Shuji, Takahashi Nobunori, Asai Nobuyuki, Yamashita Satoshi, Terabe Kenya, Matsumoto Takuya, Sobue Yasumori, Nishiume Tsuyoshi, Suzuki Mochihito, Ishiguro Naoki, Kojima Toshihisa

    MODERN RHEUMATOLOGY   Vol. 30 ( 4 ) page: 657 - 663   2020.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Modern Rheumatology  

    Objectives: To examine time trends in the characteristics of patients with rheumatoid arthritis (RA) undergoing primary total joint replacement (TJR). Methods: Biologics were approved in Japan for use in patients with RA in July 2003. A total of 403 large joints in 282 patients who underwent TJR at our institute between 1 January 2004 and 31 December 2017 were retrospectively examined. Results: A significant decreasing trend was observed in the number of TJRs performed from 2004 to 2017 (p = 0.013). No significant trend was observed in time from RA onset to TJR (p = 0.294). Age at RA onset (p = 0.034) showed a significant increasing trend, and serum C-reactive protein (CRP) levels showed a significant decreasing trend (p < 0.001). Negative CRP (defined as ≤0.3 mg/dl; partial regression coefficient (B) = 2.44, p = 0.016) was independently associated with time from RA onset to TJR as well as age at RA onset and juxta-articular osteophyte formation. Conclusion: The number of TJRs decreased since the approval of biologics in Japan, and changes were observed in the characteristics of patients with RA undergoing TJR. Negative CRP was an independent factor associated with longer time from RA onset to TJR.

    DOI: 10.1080/14397595.2019.1649111

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  18. COMPARATIVE STUDY OF PATIENT BACKGROUND AND TREATMENT OUTCOME BY BARICITINIB DOSE UNDER REAL CLINICAL CONDITIONS. Reviewed

    Nishiume T., Takahashi N., Kojima T., Asai S., Terabe K., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 1472 - 1473   2020.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1136/annrheumdis-2020-eular.3541

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  19. EFFECTIVENESS OF ABATACEPT ON CLINICAL DISEASE ACTIVITY AND RADIOGRAPHIC PROGRESSION IN RHEUMATOID ARTHRITIS PATIENTS IN DAILY CLINICAL PRACTICE IN JAPAN: COMPARISONS ACCORDING TO ACPA STATUS

    Takahashi N., Kojima T., Asai S., Terabe K., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 629 - 630   2020.6

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  20. PERIARTICULAR OSTEOPHYTE FORMATION PROTECTS AGAINST TOTAL KNEE ARTHROPLASTY IN RHEUMATOID ARTHRITIS PATIENTS WITH ADVANCED JOINT DAMAGE

    Asai S., Takahashi N., Terabe K., Kojima T., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 1384 - 1385   2020.6

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  21. THE EFFECTIVENESS OF BIOLOGICAL AGENTS CONCOMITANT WITH TACROLIMUS IN RHEUMATOID ARTHRITIS

    Terabe K., Takahashi N., Asai S., Kaneko A., Hirano Y., Kanayama Y., Yabe Y., Kojima T., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 304 - 305   2020.6

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  22. MECHANISM OF CHONDROPROTECTIVE EFFECTS OF 2-DEOXYGLUCOSE

    Terabe K., Takahashi N., Yoshifumi O., Masataka M., Knudson W., Knudson C., Kojima T., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 128 - 129   2020.6

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  23. HIGHER DOSES OF METHOTREXATE ASSOCIATED WITH DISCONTINUATION OF ORAL GLUCOCORTICOIDS AFTER INITIATION OF BIOLOGICAL DMARDS: A RETROSPECTIVE OBSERVATIONAL STUDY BASED ON DATA FROM A JAPANESE MULTICENTER REGISTRY STUDY

    Suzuki M., Kojima T., Takahashi N., Asai S., Terabe K., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 991 - 992   2020.6

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  24. PREDICTORS FOR SHORT-TERM CLINICAL EFFECTIVENESS OF BARICITINIB IN RHEUMATOID ARTHRITIS PATIENTS IN ROUTINE CLINICAL PRACTICE: DATA FROM A JAPANESE MULTICENTER REGISTRY

    Takahashi N., Kojima T., Asai S., Terabe K., Ishiguro N.

    ANNALS OF THE RHEUMATIC DISEASES   Vol. 79   page: 646 - 646   2020.6

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  25. Improvement in matrix metalloproteinase-3 independently predicts low disease activity at 52 weeks in bio-switch rheumatoid arthritis patients treated with abatacept Reviewed

    Takemoto T., Takahashi N., Kida D., Kaneko A., Hirano Y., Fujibayashi T., Kanayama Y., Hanabayashi M., Yabe Y., Takagi H., Oguchi T., Kato T., Funahashi K., Matsumoto T., Sobue Y., Nishiume T., Suzuki M., Yokota Y., Terabe K., Asai S., Ishiguro N., Kojima T.

    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY   Vol. 38 ( 5 ) page: 933 - 939   2020

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

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  26. Chondroprotective effects of 4-methylumbelliferone and hyaluronan synthase-2 overexpression involve changes in chondrocyte energy metabolism

    Terabe Kenya, Ohashi Yoshifumi, Tsuchiya Saho, Ishizuka Shinya, Knudson Cheryl B., Knudson Warren

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 294 ( 47 ) page: 17799 - 17817   2019.11

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    Language:Japanese   Publisher:Journal of Biological Chemistry  

    Hyaluronan is a critical component of articular cartilage and partially helps retain aggrecan within the extracellular matrix of this tissue. During osteoarthritis, hyaluronan and aggrecan loss are an early sign of tissue damage. However, our recent attempts to mimic hyaluronan loss with the hyaluronan inhibitor 4-methylumbelliferone (4MU) did not exacerbate arthritis-like features of in vitro models of arthritis, but surprisingly, caused the reverse (i.e. provided potent chondroprotection). Moreover, the protective effects of 4MU did not depend on its role as a hyaluronan inhibitor. To understand the molecular mechanism in 4MU-mediated chondroprotection, we considered recent studies suggesting that shifts in intracellular UDP-hexose pools promote changes in metabolism. To determine whether such metabolic shifts are associated with the mechanism of 4MU-mediated pro-catabolic inhibition, using molecular and metabolomics approaches, we examined whether bovine and human chondrocytes exhibit changes in the contribution of glycolysis and mitochondrial respiration to ATP production rates as well as in other factors that respond to or might drive these changes. Overexpression of either HA synthase-2 or 4MU effectively reduced dependence on glycolysis in chondrocytes, especially enhancing glycolysis use by interleukin-1 (IL1)-activated chondrocytes. The reduction in glycolysis secondarily enhanced mitochondrial respiration in chondrocytes, which, in turn, rescued phospho-AMP-activated protein kinase (AMPK) levels in the activated chondrocytes. Other glycolysis inhibitors, unrelated to hyaluronan biosynthesis, namely 2-deoxyglucose and dichloroacetate, caused metabolic changes in chondrocytes equivalenttothose elicited by 4MU and similarly protected both chondrocytes and cartilage explants. These results suggest that fluxes in UDP-hexoses alter metabolic energy pathways in cartilage.

    DOI: 10.1074/jbc.RA119.009556

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  27. Inhibition of CD44 intracellular domain production suppresses bovine articular chondrocyte de-differentiation induced by excessive mechanical stress loading

    Sobue Yasumori, Takahashi Nobunori, Ohashi Yoshifumi, Suzuki Mochihito, Nishiume Tsuyoshi, Kobayakawa Tomonori, Terabe Kenya, Knudson Warren, Knudson Cheryl, Ishiguro Naoki, Kojima Toshihisa

    SCIENTIFIC REPORTS   Vol. 9 ( 1 ) page: 14901   2019.10

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    Language:Japanese   Publisher:Scientific Reports  

    CD44 fragmentation is enhanced in chondrocytes of osteoarthritis (OA) patients. We hypothesized that mechanical stress-induced enhancement of CD44-intracellular domain (CD44-ICD) production plays an important role in the de-differentiation of chondrocytes and OA. This study aimed to assess the relationship between CD44-ICD and chondrocyte gene expression. Monolayer cultured primary bovine articular chondrocytes (BACs) were subjected to cyclic tensile strain (CTS) loading. ADAM10 inhibitor (GI254023X) and γ-secretase inhibitor (DAPT) were used to inhibit CD44 cleavage. In overexpression experiments, BACs were electroporated with a plasmid encoding CD44-ICD. CTS loading increased the expression of ADAM10 and subsequent CD44 cleavage, while decreasing the expression of SOX9, aggrecan, and type 2 collagen (COL2). Overexpression of CD44-ICD also resulted in decreased expression of these chondrocyte genes. Both GI254023X and DAPT reduced the production of CD44-ICD upon CTS loading, and significantly rescued the reduction of SOX9 expression by CTS loading. Chemical inhibition of CD44-ICD production also rescued aggrecan and COL2 expression following CTS loading. Our findings suggest that CD44-ICD is closely associated with the de-differentiation of chondrocytes. Excessive mechanical stress loading promoted the de-differentiation of BACs by enhancing CD44 cleavage and CD44-ICD production. Suppression of CD44 cleavage has potential as a novel treatment strategy for OA.

    DOI: 10.1038/s41598-019-50166-4

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  28. Improvement in Matrix metalloproteinase-3 Levels at 12 Weeks Independently Predicts Achievement of Low Disease Activity at 52 Weeks in Bio-switch Patients with Rheumatoid Arthritis Treated with Abatacept

    Takahashi Nobunori, Kojima Toshihisa, Terabe Kenya, Asai Shuji, Ishiguro Naoki

    ARTHRITIS & RHEUMATOLOGY   Vol. 71   2019.10

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  29. Mechanism of Chondroprotective Effects of 4-Methylumbelliferone and 2-Deoxyglucose

    Terabe Kenya, Takahashi Nobunori, Ohashi Yoshifumi, Kojima Toshihisa, Ishiguro Naoki, Knudson Cheryl, Knudson Warren

    ARTHRITIS & RHEUMATOLOGY   Vol. 71   2019.10

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  30. Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronan

    Ishizuka Shinya, Tsuchiya Saho, Ohashi Yoshifumi, Terabe Kenya, Askew Emily B., Ishizuka Naoko, Knudson Cheryl B., Knudson Warren

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 294 ( 37 ) page: 13562 - 13579   2019.9

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    Language:Japanese   Publisher:Journal of Biological Chemistry  

    Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HA synthase-2 viral overexpression; HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA >100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13, and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein (TSG6)) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1β (IL1β), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides. However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the procatabolic phenotype of neighboring nontransduced chondrocytes as we had expected. Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells. In addition, high HA biosynthesis rates, especially in transduced procatabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs.

    DOI: 10.1074/jbc.RA119.008567

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  31. The pericellular hyaluronan of articular chondrocytes

    Knudson Warren, Ishizuka Shinya, Terabe Kenya, Askew Emily B., Knudson Cheryl B.

    MATRIX BIOLOGY   Vol. 78-79   page: 32 - 46   2019.5

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    Language:Japanese   Publisher:Matrix Biology  

    The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan—with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.

    DOI: 10.1016/j.matbio.2018.02.005

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  32. Simvastatin promotes restoration of chondrocyte morphology and phenotype

    Terabe Kenya, Takahashi Nobunori, Cobb Michelle, Askew Emily B., Knudson Cheryl B., Knudson Warren

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 665   page: 1 - 11   2019.4

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    Language:Japanese   Publisher:Archives of Biochemistry and Biophysics  

    In this study we examined whether the action of simvastatin affects re-differentiation of passaged chondrocytes and if so, whether this was mediated via changes in cholesterol or cholesterol intermediates. Bovine articular chondrocytes, of varying passage number, human knee chondrocytes and rat chondrosarcoma chondrocytes were treated with simvastatin and examined for changes in mRNA and protein expression of markers of the chondrocyte phenotype as well as changes in cell shape, proliferation and proteoglycan production. In all three models, while still in monolayer culture, simvastatin treatment alone promoted changes in phenotype and morphology indicative of re-differentiation most prominent being an increase in SOX9 mRNA and protein expression. In passaged bovine chondrocytes, simvastatin stimulated the expression of SOX9, ACAN, BMP2 and inhibited the expression of COL1 and α-smooth muscle actin. Co-treatment of chondrocytes with simvastatin plus exogenous cholesterol—conditions that had previously reversed the inhibition on CD44 shedding, did not alter the effects of simvastatin on re-differentiation. However, the co-treatment of chondrocytes with simvastatin together with other pathway intermediates, mevalonate, geranylgeranylpyrophosphate and to a lesser extent, farnesylpyrophosphate, blocked the pro-differentiation effects of simvastatin. Treatment with simvastatin stimulated expression of SOX9 and COL2a and enhanced SOX9 protein in human OA chondrocytes. The co-treatment of OA chondrocytes with mevalonate or geranylgeranylpyrophosphate, but not cholesterol, blocked the simvastatin effects. These results lead us to conclude that the blocking of critical protein prenylation events is required for the positive effects of simvastatin on the re-differentiation of chondrocytes.

    DOI: 10.1016/j.abb.2019.01.038

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  33. An Open-label Single-arm Trial of a Novel Extramedullary Guide Coordinated with 3D Surgical Assistive Software for Total Knee Arthroplasty.

    Kida D, Hashimoto H, Saito AM, Kito Y, Mori K, Terabe K, Takahashi N, Tomita Y

    Acta medica Okayama   Vol. 72 ( 4 ) page: 441 - 445   2018.8

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  34. An Open-label Single-arm Trial of a Novel Extramedullary Guide Coordinated with 3D Surgical Assistive Software for Total Knee Arthroplasty

    Kida Daihei, Hashimoto Hiroya, Saito Akiko M., Kito Yukari, Mori Kouichi, Terabe Kenya, Takahashi Nobunori, Tomita Yasushi

    ACTA MEDICA OKAYAMA   Vol. 72 ( 4 ) page: 441 - 445   2018.8

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  35. An open-label single-arm trial of a novel extramedullary guide coordinated with 3D surgical assistive software for total knee arthroplasty

    Kida D., Hashimoto H., Saito A.M., Kito Y., Mori K., Terabe K., Takahashi N., Tomitae Y.

    Acta Medica Okayama   Vol. 72 ( 4 ) page: 441 - 445   2018

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    There is no assistive device for extramedullary surgery coordinated with 3D surgical assistive software for the total knee arthroplasty (TKA). We developed a novel extramedullary universal guide coordinated with 3D surgical assistive software and a novel extramedullary patient-specific assistive guide for the placement of femoral components by referring to an area not affected by cartilage or bone spurs, and filed a patent application. In this study, we visualize and reconstruct the total alignment of the lower extremity in TKA using these surgical devices, and validate their precision. A report releasing study results will be submitted in an appropriate journal.

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  36. Patient-reported outcomes as assessment tools and predictors of long-term prognosis: a 7-year follow-up study of patients with rheumatoid arthritis

    Kojima Masayo, Kojima Toshihisa, Suzuki Sadao, Takahashi Nobunori, Funahashi Koji, Asai Shuji, Yoshioka Yutaka, Terabe Kenya, Asai Nobuyuki, Takemoto Toki, Ishiguro Naoki

    INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES   Vol. 20 ( 9 ) page: 1193 - 1200   2017.9

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    Language:Japanese   Publisher:International Journal of Rheumatic Diseases  

    Objective: Whether the Boolean-based American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for rheumatoid arthritis (RA) including patient-reported outcome measures (PROMs) for remission are strict for use in daily clinical practice is controversial. This study aimed to clarify the differences in the remission status defined by the criteria, including and excluding PROMs, and to identify the baseline predictors of long-term prognosis using 7-year follow-up data. Method: A total of 103 RA outpatients completed the baseline and 7-year follow-up questionnaire surveys. Pain visual analogue scale (VAS) of ≤ 1/10 was used as a PROM criterion for remission. Results: Only 10 patients achieved full-remission, whereas 18 met the partial-remission criteria excluding PROM at baseline. Although 70.0% of those who achieved full remission at baseline had full or partial remission status, 77.8% of those with partial remission were categorized as having no remission at 7 years. Significant baseline differences in the remission status at 7 years were observed with regard to disease duration, pain VAS, and physical function (Short Form 36 [SF-36]). Stepwise logistic regression analysis adjusted for age and sex identified disease duration and general health perception (SF-36) as independent predictors of full-remission. Conclusion: Remission criteria including PROMs are stringent but important to achieve sustained remission. Early intensive treatment and efforts to improve patients’ health perceptions may result in better prognosis for RA.

    DOI: 10.1111/1756-185X.12789

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Presentations 11

  1. 軟骨細胞における細胞内代謝変動の網羅的解析による検討

    寺部 健哉

    第8回JCRベーシックリサーチカンファレンス  2021.11.12  岡田髄象

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    Event date: 2021.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB   Country:Japan  

  2. 関節リウマチに対する生物学的製剤の継続性評価 —Tsurumai Biologics Communication registry—

    寺部 健哉

    第32回中部リウマチ学会  2021.9.17  小川法良

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:アクトシティ浜松   Country:Japan  

  3. 糖尿病合併関節リウマチ患者における背景因子の検討

    寺部 健哉

    第94回日本整形外科学会学術総会  2021.5.20  土屋 弘行

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    Event date: 2021.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京国際フォーラム、JPタワーホール&カンファレンス、WEB開催   Country:Japan  

  4. 生物学的製剤におけるtacrolimus併用の有用性の検討

    寺部 健哉

    第94回日本整形外科学会学術総会  2021.5.20  土屋 弘行

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    Event date: 2021.5

    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京国際フォーラム、JPタワーホール&カンファレンス、WEB開催   Country:Japan  

  5. 生物学的製剤におけるtacrolimus併用の有用性の検討

    寺部 健哉

    第65回日本リウマチ学会  2021.4.26  竹内勤

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    Event date: 2021.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB   Country:Japan  

  6. 関節リウマチに対する生物学的製剤の継続性評価-Tsurumai Biologics Communication registryから-

    寺部 健哉

    第65回日本リウマチ学会  2021.4.26  竹内勤

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    Event date: 2021.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB   Country:Japan  

  7. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    2021.3.26 

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    Event date: 2021.3

  8. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    2020.8.17 

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    Event date: 2020.8 - 2020.9

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  9. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    eular2020  2020.6.6 

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    Event date: 2020.6

    Language:English  

  10. 生物学的製剤におけるtacrolimus併用の有用性の検討

    2020.8.17 

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    Event date: 2020.8 - 2020.9

    Language:Japanese   Presentation type:Poster presentation  

  11.  The Effectiveness of Biological Agents Concomitant with Tacrolimus in Rheumatoid Arthritis

    Kenya Terabe

    eular2020  2020.6.6 

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    Event date: 2020.6

    Language:English   Presentation type:Poster presentation  

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KAKENHI (Grants-in-Aid for Scientific Research) 6

  1. 外因性hyaluronanの軟骨細胞における役割の解明

    Grant number:20K09458  2020.4 - 2023.3

    横田 裕

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    変形性膝関節症(OA)の有効な進行抑制薬は未だ存在しない。外因性hyaluronan(HA)は、膝OAの治療薬として推奨されているが、その作用機序について明確ではない。近年の研究からOA軟骨細胞では、嫌気的解糖系の代謝(glycolysis)が亢進する代謝リプログラミングにより、炎症が惹起されることが明らかとなってきた。申請者らはin vitro実験系において外因性HAがglycolysisを阻害して抗炎症作用を発揮していることを発見した。軟骨細胞におけるHAの役割を、代謝リプログラミングからアプローチして明らかにすることで、新たな治療薬の開発につながる可能性が高いと考える。

  2. 軟骨細胞における代謝リプログラミングのメカニズムと役割の解明

    Grant number:20K18061  2020.4 - 2023.3

    科学研究費助成事業  若手研究

    寺部 健哉

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    Authorship:Principal investigator 

    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    変形性膝関節症(OA)に対する有効な進行抑制薬は未だ存在しない。これまでの研究からOA軟骨細胞では正常細胞と比較して嫌気的解糖系の代謝(glycolysis)が亢進する代謝リプログラミングが発生し、これにより炎症が惹起されていることが明らかとなった。我々はglycolysis阻害剤である2-Deoxy-D-glucoseとガラクトースが炎症下の軟骨細胞に保護作用があることを発見した。本研究ではin vitroでの新たなOA細胞モデルを使用しglycolysisの更なる機能解析をすすめ、in vivoでglycolysis阻害剤の有効性と網羅的な代謝変動を検討することを目的とする。
    本研究では、軟骨細胞の変性における代謝変動 (glycolysisの亢進、好気性代謝の抑制)の意義と代謝経路の機能解析を行い、炎症下における代謝変動の制御による関節軟骨の保護につながる薬剤の検討を行っている。
    昨年度までに我々はglycolysis阻害剤として2-deoxyglucose(2-DG)とガラクトースを主に用いて検討した。ガラクトースは2DGと同様にサフラニンO染色でIL-1β刺激による染色性の低下を抑制し、軟骨保護作用を有することを明らかにした。さらに炎症により好気性代謝が行われるミトコンドリアの障害の評価目的にこれにより産生される酸化ストレスであるreactive oxygen species(ROS)と一酸化窒素(NO)について検討した。IL-1β刺激でROS、NOともに増加したが2DGとガラクトースはともにこれを抑制し、いずれもミトコンドリアの保護作用を明らかにした。
    次にglycolysis阻害剤は炎症による軟骨細胞のエネルギー代謝のkey regulatorであるAMP-activated protein kinase (AMPK)の活性化の低下を回復させることを明らかにしており、AMPKを活性化する5-Aminoimidazole-4-Carboxamide Riboside (AICAR)の軟骨保護作用の有無について検討した。AICARは炎症によるglycolysisを阻害し軟骨分解酵素であるMMP13の発現を抑制した。さらにglycolysis阻害剤と同様に炎症下のサフラニンO染色性低下も抑制し軟骨保護作用を認めた。
    さらにガラクトースはIL-1β刺激によるAMPK活性化の低下のみならず無刺激のcontrol群のAMPK活性化させることを明らかにした。以上より2DG、ガラクトース、AICARが変形性関節症(OA)の治療に有用性を高める結果であった。
    現在までにin vitro実験については概ね予定通りに進んでいる。特にガラクトースと2DGが炎症下のglycolysis亢進の阻害に加えて、ミトコンドリアの保護作用を明らかにしており、当初の仮説含めてこれまでの研究結果と矛盾はない。さらに軟骨細胞にIL-1β刺激による2DGの効果について質量分析によるメタボローム解析を行った。現在結果の解析中であるが、glycolysisのみならず他のアミノ酸代謝なども変化していることが確認されており今後の詳細に報告する予定である。in vivoはOAマウスモデルである内側半月板不安定化(DMM)モデルを使用してガラクトースの効果を検討予定である。
    本年度までに上記検討を行ってきたことより 、来年度はin vitro、 in vivoの各々の研究を進める予定である。In vitroとして他の軟骨変性モデルとして過剰メカニカルストレスモデルと脱分化モデルを用いて行う。とくに牛関節軟骨を数回継代すると脱分化し軟骨細胞の表現型を喪失するが、通常状態でもATP産生においてglycolysisが優位である軟骨がどのように代謝変動するか確認予定である。またメタボローム解析の結果からアミノ酸代謝のうちグルタミン代謝が亢進していることを示唆する結果が得られており、当初の予定に加えてin vitroでのアミノ酸代謝変動についても検討する。方法としては2DG、ガラクトースのglycolysis阻害剤がグルタミン代謝にあたえる影響をグルタミン測定キット等を使用して糖代謝とアミノ酸代謝の関連を検討する。また今後はOAモデルマウスによるin vivo研究を進めていく。当初の予定ではガラクトースはOAマウスモデルに経口投与の予定であったが、体重変化に差による関節変性評価の影響を考慮して関節注射による投与も検討予定である。来年度は上記方法によりin vivo研究を中心に進めていく予定である。

  3. Mechanism for the Chondroprotective Effects of Glycolysis Inhibitor

    Grant number:18K16678  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Terabe kenya

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    Authorship:Principal investigator 

    Grant amount:\3380000 ( Direct Cost: \2600000 、 Indirect Cost:\780000 )

    We mainly demonstrated that inflammation by induced metabolic reprogramming which is reduced mitochondrial potential and enhanced dependence on glycolysis in chondrocytes.
    We also demonstrated that glycolysis inhibitors such as 2DG returned the cell metabolism, and reversed the pro-inflammatory agents-induced increases the expression of MMP13. Although IL-1β lost safranin O staining in cartilage samples, coincubation with glycolysis inhibitors blocked in the loss of proteoglycan. AMPK is associate with energy homeostasis in chondrocytes. IL-1β treatment decreased accumulation of phosphor AMPK but co-treatment with glycolysis inhibitors resulted in a rescue of the pAMPK status. Co treatment with AICAR, which is inducer of AMPK, also induced chonroprotective effect, glycolysis inhibitors or AICAR have chondroprotective effect by changing metabolism and upregulate AMPK.

  4. 代謝リプログラミングによる腱由来間葉系幹細胞の分化制御の解明

    Grant number:21K09274  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    浅井 秀司, 寺部 健哉

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    腱損傷部には変性と修復の両方に直接関与する特異的な間葉系幹細胞が誘導される。本研究では、この間葉系幹細胞の分化における解糖系代謝を中心とした代謝リプログラミングの機能解析を行う。また、腱損傷部の変性および修復に対する代謝リプログラミング制御の作用を明らかにする。これにより、内在性の間葉系幹細胞の分化を制御し、細胞移植を必要としない腱損傷の新たな治療法の開発につなげる。

  5. Frailty prevention program for successful aging of rheumatoid arthritis patients

    Grant number:20H03954  2020.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

  6. 代謝リプログラミング制御による軟骨破壊抑制ー新規関節リウマチ治療を目指してー

    Grant number:19K09619  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    小嶋 俊久, 寺部 健哉, 祖父江 康司

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    Authorship:Coinvestigator(s) 

    解糖系代謝リプログラミング(ミトコンドリアでの好気的解糖系から嫌気的解糖glycolysisへの変化)を制御することが、炎症、悪性腫瘍の新たな治療標的として注目されている。本研究の目的は、軟骨細胞における機械的ストレスの解糖系代謝リプログラミングへの関与を明らかにし、軟骨破壊に対するglycolysisの制御によるRA治療を目指すことである。軟骨培養、マウスモデルにおいて、glycolysis阻害薬を用いて、その治療標的としての可能性について探索する。実際の病態でのglycolysisの関与をRA滑膜、骨軟骨の免疫組織染色により検討する。
    軟骨細胞のメカニカルストレスによる代謝リプログラミングを検討するため、軟骨細胞の主たるメカノレセプターとしてTRPV-4に注目し、TRPV-4の特異的agonist(GSK101)による刺激実験を、昨年度からさらに進めて行った。ウシ関節軟骨細胞を単離し、GSK101にて刺激。より低低濃度のGSK101刺激(1nM)により、IL-1β(10ng/mL)刺激において誘導される軟骨糖代謝リプログラミングglycolysis の主たる酵素の一つであるLDHAの発現は有意に抑制され、Seahorse細胞外フラックスアナライザーを用いた実験においてもglycolysisが抑制されていることが示された。 さらにウシ滑膜細胞を用いた培養系においても、LPSを用いた炎症性刺激によりglycolysisが誘導されることを確認し、このglycolysis誘導が転写調節因子CREBと関連することも明らかにした。
    また、ヒト軟骨細胞において、IL-1β(10ng/mL)にて誘導されるMMP-13(PCR、Western blottingによる), 細胞外マトリクス成分であるプロテオグリカンの分解(DMMB assayによる)を低濃度GSK101は抑制しており、これは、GSK101による TRPV-4の活性化によるCaMKK/AMPK/NF-κB signaling pathwayを介した作用であることが明らかになった。これらの結果は2020年10月日本整形外科基礎学術集会、2021年2月にOrthopedic Research Societyにて発表された。
    In vivoの実験系については、動物実験施設は完備しており、マウスに対するメカニカルストレスモデルとして走行負荷モデルによる条件を設定し、関節炎モデルとしてcollagen-induced arthritisモデルが確立された。
    軟骨細胞モデルにおいては、一定の成果を上げることができた(論文投稿中)。
    また、動物モデルにおいては、走行モデルの条件設定、関節炎モデルを確立することができた。
    動物モデルでの検討を進める。

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