2023/04/17 更新

写真a

テラベ ケンヤ
寺部 健哉
TERABE Kenya
所属
医学部附属病院 整形外科 病院助教
職名
病院助教
外部リンク

学位 1

  1. 医学博士 ( 2016年10月   名古屋大学 ) 

研究分野 1

  1. ライフサイエンス / 整形外科学

受賞 1

  1. 第26回軟骨代謝学会賞

    2021年3月   軟骨代謝学会  

    寺部健哉

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    受賞区分:国内学会・会議・シンポジウム等の賞 

 

論文 46

  1. Reasons and risk factors for discontinuation of treatment with any biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: A long-term observational study

    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年8月

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    記述言語:日本語  

    DOI: 10.1093/mr/roac090

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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 査読有り

    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   708 巻   頁: 108962   2021年9月

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    担当区分:責任著者   記述言語:英語  

    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 査読有り

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

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 15131   2021年7月

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    担当区分:責任著者   記述言語:英語  

    DOI: 10.1038/s41598-021-94611-9

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  4. Effectiveness of tacrolimus concomitant with biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis 査読有り

    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   33 巻 ( 2 ) 頁: 292 - 301   2023年3月

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    記述言語:英語   出版者・発行元:Modern rheumatology  

    OBJECTIVES: The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. METHODS: 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. RESULTS: Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. CONCLUSIONS: Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

    DOI: 10.1093/mr/roac025

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  5. Factors associated with frailty in rheumatoid arthritis patients with decreased renal function 査読有り

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

    MODERN RHEUMATOLOGY   33 巻 ( 2 ) 頁: 323 - 329   2023年3月

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    記述言語:英語   出版者・発行元:Modern rheumatology  

    OBJECTIVES: To investigate factors associated with frailty in rheumatoid arthritis (RA) patients with decreased renal function. METHODS: RA patients who visited outpatient clinics from June to August 2021 were included (N = 625). Patients with estimated glomerular filtration rate <60 ml/min/1.73 m2 were defined as having decreased renal function (N = 221) and divided into the non-frailty (N = 153) and frailty (N = 58) groups. Patient characteristics were compared between the two groups by univariate analysis. Significant factors in univariate analysis were assessed by logistic regression analysis to determine their association with frailty in patients with decreased renal function. RESULTS: Patients in the frailty group were older (74.0 vs.79.0 years) and had a longer duration of disease (11.1 vs. 17.8 years), higher Disease Activity Score erythrocyte sedimentation rate (DAS28-ESR; 2.99 vs. 3.80), higher Health Assessment Questionnaire Disability Index (0.42 vs. 1.43), and a lower rate of methotrexate (MTX) use (46.4% vs. 25.9) compared to those in the non-frailty group. Factors associated with frailty in patients with decreased renal function were age (odds ratio: 1.07), duration of disease (1.06), DAS28-ESR (1.85), and MTX use (0.42). CONCLUSIONS: Among factors associated with frailty in RA patients with decreased renal function, improving DAS28-ESR is likely to be the most feasible approach to promote recovery from frailty (200/200 words).

    DOI: 10.1093/mr/roac018

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  6. Periprosthetic humeral fracture revision using a massive allograft in a patient with rheumatoid arthritis: A case report

    Kishimoto Kenji, Kojima Toshihisa, Takahashi Nobunori, Asai Shuji, Terabe Kenya, Suzuki Mochihito, Ohashi Yoshifumi, Kihira Daisuke, Maeda Masataka, Tatebe Masahiro, Imagama Shiro

    MODERN RHEUMATOLOGY CASE REPORTS     2023年1月

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  7. Validation of grip strength as a measure of frailty in rheumatoid arthritis

    Sobue Yasumori, Suzuki Mochihito, Ohashi Yoshifumi, Koshima Hiroshi, Okui Nobuyuki, Funahashi Koji, Ishikawa Hisato, Inoue Hidenori, Kojima Masayo, Asai Shuji, Terabe Kenya, Kishimoto Kenji, Maeda Masataka, Kihira Daisuke, Imagama Shiro, Kojima Toshihisa

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 21090   2022年12月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    Rheumatoid arthritis (RA) patients often exhibit finger/wrist joint symptoms and reduced grip strength. This study aimed to validate grip strength as a measure of frailty in RA patients. Subjects were 424 female RA patients (mean age ± standard deviation, 66.8 ± 14.5 years). Frailty was defined as a score of ≥ 8 points on the Kihon Checklist (KCL). Finger/wrist joint symptoms were defined based on tender or swollen joints. Associations between frailty and grip strength were determined using receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis. There were 179 subjects with frailty (42.2%). Multivariable logistic regression analysis revealed that frailty was significantly associated with grip strength independently of finger/wrist joint symptoms. In ROC curves, cut-off scores of grip strength for frailty in subjects without and with finger/wrist joint symptoms were 17 kg (sensitivity, 62.1%; specificity, 69.0%) and 14 kg (sensitivity, 63.2%; specificity, 73.0%), respectively. The results of the present study suggest that grip strength in female RA patients is associated with frailty, with a cut-off score of 17 kg (equivalent to Cardiovascular Health Study criteria, < 18 kg) when RA patients have no finger/wrist joint symptoms. However, when RA patients have finger/wrist joint symptoms, it may be considered to reduce the cut-off score of grip strength.

    DOI: 10.1038/s41598-022-21533-5

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  8. Disease activity at baseline is an independent predictor of frailty at one year in pre-frail patients with rheumatoid arthritis; a multicenter retrospective observational study.

    Ohashi Y, Takahashi N, Sobue Y, Suzuki M, Hattori K, Kishimoto K, Terabe K, Asai S, Kojima T, Kojima M, Imagama S

    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association     2022年11月

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    記述言語:英語   出版者・発行元:Journal of Orthopaedic Science  

    Objectives: To investigate factors predicting frailty for one year in pre-frail patients with rheumatoid arthritis (RA). Method: A total of 298 RA patients who were pre-frail in 2020 were evaluated in this structured, retrospective observational study. Of the 298 patients, 42 who were frail and 256 who were not in 2021 were assigned to the frailty and non-frailty groups, respectively. After comparing characteristics of both groups using univariate analysis, predictive factors of frailty were assessed by logistic regression analysis. The proportion of frail patients in 2021 by DAS28-ESR level in 2020 was examined by the Cochran-Armitage trend test and chi-squared test. After dividing pre-frail patients into those with DAS28-ESR ≥3.2 and DAS28-ESR <3.2 in 2020, one-year change in DAS28-ESR in the frailty and non-frailty groups for both subgroups were compared by the paired t-test. Results: The frailty group was older (mean: 71.0 vs. 65.4 years) and had a higher DAS28-ESR (mean: 3.22 vs. 2.70) than the non-frailty group. DAS28-ESR was identified as a predictive factor for frailty (OR: 1.49). Among patients with DAS28-ESR ≥3.2 in 2020, DAS28-ESR improved in the non-frailty group in 2021 (mean: 3.97 in 2020 vs. 3.13 in 2021) but did not in the frailty group (3.97 in 2020 vs. 3.81 in 2021). Among those with DAS28-ESR <3.2 in 2020, DAS28-ESR was unchanged in the non-frailty group in 2021 (2.15 in 2020 vs. 2.23 in 2021) but increased in the frailty group (2.53 in 2020 vs. 3.23 in 2021). Conclusions: Disease activity at baseline is an independent predictor of frailty one year later in pre-frail patients with RA.

    DOI: 10.1016/j.jos.2022.10.025

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  9. Locomotive syndrome in rheumatoid arthritis patients during the COVID-19 pandemic

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

    NAGOYA JOURNAL OF MEDICAL SCIENCE   84 巻 ( 4 ) 頁: 799 - 812   2022年11月

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    記述言語:英語   出版者・発行元:Nagoya Journal of Medical Science  

    This study aimed to longitudinally evaluate the development of locomotive syndrome (LS) in rheumatoid arthritis (RA) patients during the COVID-19 pandemic using the 25-question Geriatric Locomotive Function Scale (GLFS-25). Subjects were 286 RA patients (female, 70.6%; mean age, 64.2 years) who had GLFS-25 and Clinical Disease Activity Index (CDAI) data available for a 1-year period during the COVID-19 pandemic and who did not have LS at baseline. Associations between subject characteristics and development of LS were determined using logistic regression analysis. Among the 286 patients, 38 (13.3%, LS group) developed LS at 1 year after baseline. In the LS group, scores of the GLFS-25 categories “GLFS-5” and “Social activities” were significantly increased at 1 year relative to baseline. GLFS-5 is a quick 5-item version of the GLFS-25, including questions regarding the difficulty of going up and down stairs, walking briskly, distance able to walk without rest, difficulty carrying objects weighing 2 kg, and ability to carry out load-bearing tasks and housework. A significant correlation was also observed between changes in “Social activities” and that of “GLFS-5.” Multivariable logistic regression analysis revealed that the development of LS was significantly associated with BMI (OR: 1.11 [95% confidence interval (CI): 1.00–1.22]) and CDAI (OR: 1.08 [95%CI: 1.00–1.16]) at baseline. Adequate exercise and tight control of RA disease activity are important for preventing the development of LS in view of restrictions on going out imposed during the COVID-19 pandemic. GLFS-5 is useful for evaluating the physical function of RA patients.

    DOI: 10.18999/nagjms.84.4.799

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  10. Increased prevalence of Staphylococcus aureus nasal carriage in rheumatoid arthritis patients with moderate/high disease activity.

    Asai S, Takahashi N, Kishimoto K, Suzuki M, Ohashi Y, Terabe K, Kojima T, Imagama S

    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association     2022年10月

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    記述言語:英語   出版者・発行元:Journal of Orthopaedic Science  

    Background: Staphylococcus aureus (S. aureus) nasal carriage is a well-known risk factor for surgical site infection (SSI) after total joint arthroplasty. This study aimed to compare the prevalence of S. aureus nasal carriage between patients with osteoarthritis (OA), a degenerative joint disease, and those with rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease, who underwent total joint arthroplasty, and to investigate the influence of RA disease activity on nasal carriage rate. Methods: This retrospective study targeted 508 OA and 107 RA patients who underwent S. aureus nasal screening prior to primary total knee and/or hip arthroplasty. RA patients were divided into two groups based on disease activity: the remission/low disease activity (REM/LDA) group and the moderate/high disease activity (MDA/HDA) group. Factors associated with S. aureus nasal carriage were assessed with multivariate logistic regression models. Results: Of all 615 patients, 155 (25%) carried S. aureus in their nares. Compared to OA patients, RA patients had a significantly higher rate of S. aureus nasal carriage (24% vs. 33%, p = 0.049). Compared to the REM/LDA group (n = 39), the MDA/HDA group (n = 58) had a significantly higher rate of S. aureus nasal carriage (21% vs. 41%, p = 0.032). Multivariate analysis revealed that the MDA/HDA group, but not the REM/LDA group, had a significantly higher odds of S. aureus nasal carriage compared to the OA group (odds ratio: 2.76, 95% confidence interval: 1.07–7.12). Conclusion: Preoperative nasal screening for S. aureus is beneficial, especially in RA patients with moderate/high disease activity.

    DOI: 10.1016/j.jos.2022.09.014

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  11. Association between locomotive syndrome and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients: A retrospective observational study

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

    GERIATRICS & GERONTOLOGY INTERNATIONAL   22 巻 ( 10 ) 頁: 904 - 906   2022年10月

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    記述言語:日本語   出版者・発行元:Geriatrics and Gerontology International  

    DOI: 10.1111/ggi.14475

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  12. Age and symptoms at onset of ankylosing spondylitis in Japanese patients

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

    MODERN RHEUMATOLOGY     2022年8月

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    記述言語:日本語  

    DOI: 10.1093/mr/roac081

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  13. Influence of frailty on patient global assessment in rheumatoid arthritis 査読有り

    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   22 巻 ( 5 ) 頁: 399 - 404   2022年5月

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  14. Changes in perioperative C-reactive protein levels in patients with rheumatoid arthritis undergoing total knee arthroplasty in the biologic era

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

    NAGOYA JOURNAL OF MEDICAL SCIENCE   84 巻 ( 2 ) 頁: 286 - 300   2022年5月

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    記述言語:日本語   出版者・発行元:Nagoya Journal of Medical Science  

    This study aimed to investigate changes in and factors associated with perioperative serum C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients undergoing total knee arthroplasty (TKA) in the biologic era. A total of 173 patients (228 knees) with RA underwent elective primary TKA at our institute between January 1, 2006 and December 31, 2018. Of these, 214 cases among 161 patients were examined in this retrospective study after excluding 3cases among 3 patients who developed postoperative complications and 11 cases among 9 patients who were treated with tocilizumab. Factors associated with changes in CRP levels between baseline (preoperative) and day 7 after TKA [∆CRP (0–7days)] were assessed by multiple regression analysis. Median (interquartile range) CRP levels were 0.69 (0.21, 1.82) mg/dl preoperatively, 5.66 (4.21, 7.61) mg/dl on postoperative day 1, 12.75 (9.79, 16.74) mg/dl on postoperative days 3–4, 3.26 (2.21, 4.85) mg/dl on postoperative day 7, and 0.87 (0.45, 1.81) mg/dl on postoperative day 14. Multivariate regression analysis revealed that body mass index ≥25 [partial regression coefficient (B)=1.03, P=0.012] and use of glucocorticoids (B=–0.86, P=0.017) were independently associated with ∆CRP (0–7days), whereas use of methotrexate and targeted drug modifying antirheumatic drugs and preoperative CRP levels (an objective biomarker of RA activity) were not. In conclusion, serum CRP levels increased rapidly after TKA and peaked on postoperative days 3–4, followed by a return to preoperative levels by postoperative day 14 in patients with RA. Obesity and the use of glucocorticoids were independently associated with changes in CRP levels.

    DOI: 10.18999/nagjms.84.2.286

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  15. Relationship between locomotive syndrome and frailty in rheumatoid arthritis patients by locomotive syndrome stage 査読有り

    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   32 巻 ( 3 ) 頁: 546 - 553   2022年4月

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    記述言語:日本語   出版者・発行元:Modern Rheumatology  

    Objectives: This study aimed to evaluate the association between locomotive syndrome (LS) and frailty in rheumatoid arthritis (RA) patients. Methods: Subjects were 538 RA patients (female, 72.9%; mean age ± standard deviation, 66.8 ± 13.4 years). LS and frailty were defined as ≥16 points on the 25-question Geriatric Locomotive Function Scale (Stage ≥2) and ≥8 points on the Kihon Checklist (KCL), respectively. Results: There were 214 subjects with Stage ≥2 LS (39.8%) and 213 subjects with frailty (39.6%). Among subjects with Stage 0, 1, 2, and 3 LS, 11.0%, 21.9%, 48.3%, and 84.6% had frailty, respectively. The KCL points for cognitive and psychosocial factors had no significant differences across LS stages. Multivariable logistic regression analysis revealed that the Health Assessment Questionnaire was independently associated with frailty and LS stage, and the Clinical Disease Activity Index was associated with LS stage but not frailty. Conclusions: As LS worsens in RA patients, the likelihood of developing physical frailty increases. RA patients with a low LS stage can still develop frailty, and suppressing disease activity may not be sufficient to prevent frailty. These findings highlight the need to screen for frailty in RA patients and consider appropriate interventions based on each patient's condition, focusing on nonphysical factors.

    DOI: 10.1093/mr/roab024

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  16. 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.

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

    The Kurume medical journal   67 巻 ( 1 ) 頁: 31 - 40   2022年3月

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    記述言語:英語   出版者・発行元:Kurume Medical Journal  

    Summary: 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% confidence 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.

    DOI: 10.2739/kurumemedj.MS671002

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  17. Comparison of the effects of baricitinib and tocilizumab on disease activity in patients with rheumatoid arthritis: a propensity score matching analysis 査読有り

    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   40 巻 ( 8 ) 頁: 3143 - 3151   2021年8月

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

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

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 15508   2021年7月

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  19. 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 査読有り

    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   31 巻 ( 4 ) 頁: 796 - 802   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/14397595.2021.1879428

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  20. REASONS AND RISK FACTOR FOR DISCONTINUATION OF BIOLOGIC AGENTS FOR RHEUMATOID ARTHRITIS PATIENTS IN LONG-TERM OBSERVATION

    Terabe K., Takahashi N., Asai S., Hirano Y., Kanayama Y., Kojima T.

    ANNALS OF THE RHEUMATIC DISEASES   80 巻   頁: 1142 - 1143   2021年6月

  21. Relationship between disease activity of rheumatoid arthritis and development of locomotive syndrome: A five-year longitudinal cohort study 査読有り

    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   31 巻 ( 1 ) 頁: 101 - 107   2021年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  22. Predictors for clinical effectiveness of baricitinib in rheumatoid arthritis patients in routine clinical practice: data from a Japanese multicenter registry 査読有り

    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   10 巻 ( 1 ) 頁: 21907   2020年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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.

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  23. A retrospective analysis of the relationship between anti-cyclic citrullinated peptide antibody and the effectiveness of abatacept in rheumatoid arthritis patients 査読有り

    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   10 巻 ( 1 ) 頁: 19717   2020年11月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    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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  24. 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   39 巻 ( 11 ) 頁: 3331 - 3339   2020年11月

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    記述言語:日本語   出版者・発行元: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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  25. Improvement in matrix metalloproteinase-3 independently predicts low disease activity at 52 weeks in bio-switch rheumatoid arthritis patients treated with abatacept 査読有り

    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   38 巻 ( 5 ) 頁: 933 - 939   2020年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  26. 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   38 巻 ( 5 ) 頁: 933 - 939   2020年9月

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    記述言語:英語  

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  27. 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   30 巻 ( 4 ) 頁: 657 - 663   2020年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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.

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  28. COMPARATIVE STUDY OF PATIENT BACKGROUND AND TREATMENT OUTCOME BY BARICITINIB DOSE UNDER REAL CLINICAL CONDITIONS. 査読有り

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

    ANNALS OF THE RHEUMATIC DISEASES   79 巻   頁: 1472 - 1473   2020年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1136/annrheumdis-2020-eular.3541

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  29. 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   79 巻   頁: 128 - 129   2020年6月

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  30. 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   79 巻   頁: 991 - 992   2020年6月

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  31. 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   79 巻   頁: 629 - 630   2020年6月

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  32. 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   79 巻   頁: 1384 - 1385   2020年6月

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  33. 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   79 巻   頁: 304 - 305   2020年6月

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  34. 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   79 巻   頁: 646 - 646   2020年6月

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

    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   38 巻 ( 5 ) 頁: 933 - 939   2020年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  36. 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   294 巻 ( 47 ) 頁: 17799 - 17817   2019年11月

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    記述言語:日本語   出版者・発行元: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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  37. 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   9 巻 ( 1 ) 頁: 14901   2019年10月

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    記述言語:日本語   出版者・発行元: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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  38. 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   71 巻   2019年10月

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    記述言語:日本語  

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  39. 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   71 巻   2019年10月

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    記述言語:日本語  

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  40. 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   294 巻 ( 37 ) 頁: 13562 - 13579   2019年9月

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    記述言語:日本語   出版者・発行元: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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  41. The pericellular hyaluronan of articular chondrocytes

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

    MATRIX BIOLOGY   78-79 巻   頁: 32 - 46   2019年5月

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    記述言語:日本語   出版者・発行元: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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  42. 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   665 巻   頁: 1 - 11   2019年4月

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    記述言語:日本語   出版者・発行元: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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  43. 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   72 巻 ( 4 ) 頁: 441 - 445   2018年8月

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  44. 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   72 巻 ( 4 ) 頁: 441 - 445   2018年8月

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  45. 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   72 巻 ( 4 ) 頁: 441 - 445   2018年

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    記述言語:日本語   出版者・発行元:Acta Medica Okayama  

    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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  46. 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   20 巻 ( 9 ) 頁: 1193 - 1200   2017年9月

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    記述言語:日本語   出版者・発行元: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

    Web of Science

    Scopus

    PubMed

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講演・口頭発表等 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年11月12日  岡田髄象

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    開催年月日: 2021年11月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:WEB   国名:日本国  

  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年9月17日  小川法良

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    開催年月日: 2021年9月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:アクトシティ浜松   国名:日本国  

  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年5月20日  土屋 弘行

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    開催年月日: 2021年5月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地: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   国名:日本国  

  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年5月20日  土屋 弘行

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    開催年月日: 2021年5月

    記述言語:日本語   会議種別:ポスター発表  

    開催地: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   国名:日本国  

  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年4月26日  竹内勤

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    開催年月日: 2021年4月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:WEB   国名:日本国  

  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年4月26日  竹内勤

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    開催年月日: 2021年4月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:WEB   国名:日本国  

  7. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    2021年3月26日 

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    開催年月日: 2021年3月

  8. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    2020年8月17日 

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    開催年月日: 2020年8月 - 2020年9月

    記述言語:英語   会議種別:口頭発表(一般)  

    国名:日本国  

  9. Mechanisms of chondroprotective effects of 2-deoxyglucose

    Kenya Terabe

    eular2020  2020年6月6日 

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    開催年月日: 2020年6月

    記述言語:英語  

  10. 生物学的製剤におけるtacrolimus併用の有用性の検討

    2020年8月17日 

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    開催年月日: 2020年8月 - 2020年9月

    記述言語:日本語   会議種別:ポスター発表  

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

    Kenya Terabe

    eular2020  2020年6月6日 

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    開催年月日: 2020年6月

    記述言語:英語   会議種別:ポスター発表  

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科研費 6

  1. 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

    研究課題/研究課題番号:18K16678  2018年4月 - 2021年3月

    科学研究費助成事業  若手研究

    寺部 健哉

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    担当区分:研究代表者 

    配分額:3380000円 ( 直接経費:2600000円 、 間接経費:780000円 )

    本研究期間において、軟骨細胞の炎症下において細胞内の代謝リプログラミングが発生しglycolysisが亢進することを確認した。更に2DG、DCA、ガラクトースなどのglycolysis阻害剤が代謝変動を介して抗炎症効果、軟骨保護作用を有することを明らかにした。本研究ではglycolysis阻害剤の効果発現メカニズムを検討した結果、AMPKが代謝リプログラミングを制御している結果が得られ、さらにAMPKの活性化を亢進させる作用を持つAICARが軟骨保護作用を有することを明らかにした。軟骨変性において代謝リプログラミングが発生し、これを制御することで軟骨を保護できる可能性を示した。
    OAは一般的な関節障害である一方で、これまでに臨床応用されているのは高分子ヒアルロン酸の関節内注射のみであり、変性進行を制御する薬物治療の確立には至っていない。OAはメタボリックシンドロームに共通する慢性炎症を基盤とした全身性疾患ととらえられるようになっており、この観点からも軟骨変性において代謝リプログラミングが関与していることを本研究で明らかにしたことは重要である。さらにこの代謝を制御して効果を発現する2DG、ガラクトースやAICARが軟骨保護作用を有することを明らかにしたのは画期的である。これによりOAの病因、病態理解につながるのみならず、新たなOA治療薬に発展することが期待できる。

  2. 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

    研究課題/研究課題番号:21K09274  2021年4月 - 2024年3月

    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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    担当区分:研究分担者 

    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。
    腱は自己修復能に乏しく,外傷や酷使により損傷すると軟骨化生や異所性骨化などの変性を生じやすい.細胞内エネルギー代謝は,細胞の分化や増殖を調整する重要な因子であり様々な刺激により変化(代謝リプログラミング)する.研究代表者らはこれまでに,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ことを明らかにした.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検討する.2021年度の研究により以下の結果を得た.
    ① CD-1マウスのアキレス腱損傷部から単離した損傷腱由来間葉系幹細胞をmicro mass cultureにより軟骨細胞へ分化誘導し,細胞外フラックスアナライザーにより解糖系代謝の変化を検討した.損傷腱由来間葉系幹細胞は軟骨分化誘導するとglycolysisが亢進することが確認された.
    ② 上記の実験系にglycolysis阻害剤である2-deoxy-D-glucose(2-DG)を添加すると,アルシアンブルー染色のintegrated densityは減少した.また,軟骨分化マーカーであるaggrecan,Sox9,II型コラーゲンの遺伝子発現量は2-DG添加により減少した.これらの結果により,損傷腱由来間葉系幹細胞の軟骨分化にglycolysisが関与することが示された.
    ③ 本研究ではglycolysisを制御する物質としてヒアルロン酸に注目している.アキレス腱損傷モデルマウスにヒアルロン酸を局所投与したところ, vehicle投与群に比べ異所性骨化の体積が統計学的有意に小さかった.組織学的評価において,ヒアルロン酸投与群ではvehicle投与群に比べ腱損傷部の軟骨様組織および骨様組織が少なかった.
    2021年度の研究成果は,本研究の根幹をなし今後の研究につながるものである.当初の計画と前後している部分もあるが,全体としてみれば研究は概ね順調に進んでいる.
    2021年度に実施を計画していたメタボローム解析は,2022年度以降に行う予定である.正常腱および損傷腱由来間葉系幹細胞の糖,脂質,アミノ酸代謝,TCA回路などの発現解析を同時に行い,解糖系を含む様々な代謝の変化と相互作用を網羅的に解析する計画である.
    また,ヒアルロン酸の軟骨分化抑制作用におけるglycolysisの関与を検討するため,細胞外フラックスアナライザーにより解糖系代謝の変化を検討し,リアルタイムPCRによりglycolysis関連遺伝子の発現を検討することを計画している.

  3. 関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築

    研究課題/研究課題番号:20H03954  2020年4月 - 2025年3月

    科学研究費助成事業  基盤研究(B)

    小嶋 雅代, 小嶋 俊久, 寺部 健哉, 永吉 真子, 竹内 研時, 近藤 克則, 大塚 礼, 斎藤 民, 松井 康素, 安岡 実佳子, 渡邉 良太

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    担当区分:研究分担者 

    関節リウマチ(RA)は代表的な慢性炎症性の運動器疾患であり、加齢と共に心身の脆弱性が増した状態「フレイル」に陥るリスクが高い。一般高齢者では「地域とのつながり・社会参加」にフレイル・介護予防効果があることが実証されており、現在、様々な住民主体の地域活動が展開されている。本研究では、RA患者においても「地域とのつながり・社会参加」がフレイルと関連するのかを検証し、その結果をふまえ、主治医を介した地域におけるフレイル・介護予防プログラムを開発し、効果検証を行う。治療中の患者であっても自分らしさを保ちながら老いる「Successful Aging」を可能とする社会の実現を目指す。
    1.既存の大規模長期縦断疫学研究NILS-LSAのデータからRA患者42人を特定し、性と年齢をマッチさせた対照群84人を選び、身体機能と認知機能の経変変化を比較した。その結果、高齢者では両群とも骨格筋量、握力、歩行速度のいずれも加齢と共に低下し、握力では有意な交互作用が見られ、非RA群の方が低下速度が大きかった。非高齢者では握力のみ加齢と共に低下し、RAの有無では差がなかった。認知機能については両群は同じように変化し、有意差はなかった。
    2.2019年度に実施されたJAGES健康とくらしの調査のデータから、要介護認定を受けていない65歳以上の高齢者のうち、関節リウマチの診断の有無について回答した23,494人を解析対象として分析した。基本チェックリスト(KCL)8点以上の場合をフレイルと定義した。全体の2.4%(571人)がRAで治療中と回答した。RAの診断を受けたことのある者はフレイル該当者が多く、主治医を中心とした包括的な介護予防対策が有効である可能性が示唆された。また、治療を中断した者に対する社会的なサポートの必要性が確認された。
    3.大学病院に通院中の40~79歳のRA患者を対象に1年半後の追跡調査を行った。全体で293人のうち、ベースラインでフレイル(KCL8点以上)に該当した者は23.2%(68人)を占めた。フレイルは、性、年齢、学歴、配偶者の有無を調整しても、1年後のリウマチ症状の増悪と有意な関連を示した(OR=2.28、95%CI=1.04―4.98)。KCLで評価したフレイルは、RA患者の予後予測指標として有用である可能性が示された。「筋力トレーニングをしている」と回答した者は、全体では12.3%(36人)あった。
    NILS-LSAのデータの分析は、ほぼ予定通りに終え、論文化の段階である。
    JAGES健康とくらしの調査2019のデータ分析についても、分析をほぼ終えている。
    COVID-19対応のため、名古屋大学で新たに行う調査の開始が少し遅れた。しかしながら、現在は軌道に乗り、順調にデータの収集が行われている。
    疫学者1名を新たな研究分担者に迎え、これまでに収集されたデータの分析および論文化を進めていく。
    名古屋市内の医療機関で診療に従事するリウマチ専門医に、65歳以上のRA患者の通院状況調査及び介入研究参加者のリクルートを依頼する。
    JAGES研究名古屋プロジェクト参加研究者の協力の下、名古屋市内で行われている通いの場の活動状況を調査し、RA患者が参加可能な通いの場のリストを作成する

  4. 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

    研究課題/研究課題番号:20K18061  2020年4月 - 2023年3月

    科学研究費助成事業  若手研究

    寺部 健哉

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    担当区分:研究代表者 

    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    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。
    これまでにglycolysis阻害剤として2-deoxyglucose(2-DG)とガラクトースの軟骨保護作用のメカニズムについて検討した。昨年度は質量分析によるメタボローム解析を行い、炎症下の軟骨細胞におけるglycolysis阻害剤の代謝変動への影響を網羅的に解析した。glycolysisの最終産物であるlactateはIL-1β刺激で亢進したが、2DGとガラクトースはこれを抑制した。またglycolysis阻害剤はIL-1β刺激によるTCA回路、アミノ酸分解、ペントース経路の亢進をいずれも抑制し、解糖系以外にも複数の代謝変動に影響を及ぼすことを明らかにした。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のアゴニストである5-Aminoimidazole-4-Carboxamide Riboside (AICAR)を用いて検討した。AICARはIL-1β刺激によるAMPK活性化の低下を抑制した。さらにAICARは軟骨片の炎症によるサフラニンO染色性低下も抑制し軟骨保護作用を認めた。さらにメタボローム解析でglycolysis阻害剤と同様にlactateの産生を抑制した。
    次にin vivo研究として変形性関節症(OA)モデルである関節不安定化(DMM)モデルマウスを用いて、glycolysis阻害剤の関節注射の有用性について検討した結果、2DGとガラクトースは部分的に軟骨変性を抑制する傾向を示した。
    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2DGとガラクトースはメタボローム解析においてglycolysisの最終産物であるlactateはIL-1β刺激による産生亢進を抑制していたが、他の代謝の炎症による変化についても影響していることが明らかとなり、更なる研究の発展につながる可能性を示した。現在、メタボローム解析に加えて同条件下に網羅的な遺伝子発現の解析目的にRNA-seqによる検討を行っている。AICARは研究開始前に仮説通りに軟骨保護作用を有し、glycolysis阻害剤と同様に炎症下のlactateの産生亢進を抑制した。さらにflux analyzerで細胞内代謝変動を解析した結果、glycolysis阻害剤と同様にglycolysis亢進を抑制したことを確認した。in vivo研究としてOAマウスモデルを作成し、2DG、ガラクトース、AICARの関節注射の効果を検討中である。
    本年度までに上記検討を行った結果、来年度はin vitro、 in vivoの各々について以下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、これにより細胞内代謝変動がどのように変化をするかglycolysis関連遺伝子の発現とflux analyzerによるglycolysisと好気性代謝の変動について確認する予定である。次に2DG、ガラクトース、AICARはメタボローム解析を行った結果、解糖系以外の代謝変動も制御していることが明らかになったことから、この代謝産物に関連する遺伝子群を網羅的に解析するためにRNA-seq法を行った。本年度はこの結果をメタボローム解析の結果と統合する解析を進める予定である。これによりマルチオミクス解析となり、軟骨変性における細胞内代謝変動の役割の解明につながると考える。さらに現在、他の代謝としてグルタミン代謝と脂肪酸代謝の阻害剤を使用して検討したところ、glycolysis阻害剤と同様に軟骨保護作用を有する結果を得られており、そのメカニズムをglycolysis阻害剤と比較して検討していく。特に、これらの細胞内代謝変動を制御するAMPKが重要な役割を果たしているため、上記試薬の各々についてAMPKの活性化のメカニズムを明らかにすることを目標とする。
    In vivo研究としてDMMマウスモデルを用いてglycolysis阻害剤の関節注射が軟骨変性を抑制する傾向を示す結果が得られているが、本年度は検体数を増やし、X線学的、組織学的検討を進める。さらにglycolysis阻害剤に加えて、AICARとグルタミン代謝阻害剤、脂肪酸代謝阻害剤について同様にDMMマウスモデルに対する関節注射の有用性についても検討する予定である。

  5. 外因性hyaluronanの軟骨細胞における役割の解明

    研究課題/研究課題番号:20K09458  2020年4月 - 2021年3月

    科学研究費助成事業  基盤研究(C)

    横田 裕, 寺部 健哉, 高橋 伸典

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    担当区分:研究分担者  資金種別:競争的資金

    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。
    本研究では高分子ヒアルロン酸(HA)の関節軟骨保護作用の発現において代謝リプログラミングの制御が重要な役割を果たしていると考え、その機能解析を行い未だ明らかとなっていないHAの効果発現メカニズムについて検討している。とくに糖代謝における炎症による好気性代謝の抑制と嫌気性代謝(glycolysis)の亢進が重要と考え、HAによる代謝変動の制御について検討した。これまでの研究成果として軟骨細胞にIL-1βで刺激すると軟骨分解酵素であるMMP13の発現が亢進するが、HAはこれを抑制した。同時にglycolysis関連遺伝子であるglucose transporter 1(GLUT1), hexokinase 2(HK2)やLactate Dehydrogenase Asubunit(LDHA)はIL-1β刺激で発現亢進したがHAはいずれも抑制した。またIL-1β刺激によりglycolysisの最終産物であるlactateについて細胞外への分泌を評価するlactate assayで確認したところHAは培養液中のlactate分泌を抑制した。さらにHAのレセプターであるCD44とICMA-1を抗体投与しブロックした上でIL-1β刺激を行った結果HAによるMMP13とlycolysis関連遺伝子の発現抑制効果はCD44のみで阻害された。これらよりHAのglycolysis阻害効果はCD44との結合を介していることを明らかにした。これまでの結果からHAはCD44との結合を介してglycolysis阻害することによって抗炎症効果を発揮することを明らかにした。高分子HAは変形性膝関節症に対して関節注射として一般臨床で多くの患者に使用されているが詳細な効果発現メカニズムは不明である。今回の細胞内の代謝リプログラミングの関与についてはこれまでに報告はなく、メカニズムの解明に近づくものである。

  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

    研究課題/研究課題番号:19K09619  2019年4月 - 2023年3月

    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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    担当区分:研究分担者 

    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。
    我々は、滑膜炎抑制、軟骨破壊抑制をともに可能とする治療標的として、代謝リプログラミングの制御に注目し、in vitroでの検証を重ねてきた。
    1)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)による刺激実験行った。ヒト軟骨細胞において、IL-1β(10ng/mL)にて誘導されるMMP-13, 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を明らかにした(Hattori et al. Sci Rep 2021)。2)滑膜細胞における制御のメカニズムとして、LPS刺激により起こるglycolysisは、2DGにより抑制され、重要な転写調節因子であるCREBを調節することを示した(Kishimoto et al. Arch Biochem Biophy 2021)。3)炎症サイトカイン刺激による軟骨細胞培養系では、グルコースの取入れに競合すると考えられるgalactoseの添加により、glycolysisの制御、軟骨破壊抑制が可能であることを証明した(Ohashi et al. Sci Rep 2021)。4)さらにglutaminolysisの制御により、glycolysisも抑制され、軟骨破壊抑制ができることを検証した(Kihira et al. paper in preparation)
    In vivoの実験系では、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加え、半月板損傷による負荷モデルの作成を確立した。
    in vitro 軟骨細胞、滑膜細胞を用いた実験系においては、成果を論文投稿することができた。
    glycolysisのみならず、アミノ酸代謝、脂肪酸代謝制御による効果も検討している。炎症性サイトカインによる代謝変化、および代謝阻害薬の効果を糖、アミノ酸、脂肪酸代謝を網羅的に把握するためにメタボローム解析を行った。研究は発展的に進捗している。
    in vivoの実験系として、走行モデル、関節炎モデルを確立してきた。実験系が進めやすい、半月板切除による関節症モデルも導入し、関節炎、関節症モデルにおける、軟骨細胞の代謝変化、その阻害薬による、軟骨破壊抑制効果を検証する予定である。
    in vitroについては、代謝変化について網羅的(オミクス)解析を追加して行う。

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