研究者紹介システム
| 吉田 幸祐 |  |
| ヨシダ コウスケ | |
| 大学院保健学研究科 保健学専攻 | |
| 助教 | |
| 保健その他 |
研究活動
研究分野
受賞
論文
- 2021年11月, Parkinsonism & Related Disorders
[査読有り]
研究論文（学術雑誌）
Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis, and treatment of RA has highly varied outcomes. cfDNA in patients with RA is elevated in peripheral blood and synovial fluid and is associated with disease activity. Profiling of cfDNA in patients with RA may then be utilized in various aspects of clinical practice, such as the prediction of prognosis and treatment responses; monitoring disease state; and as a diagnostic marker. In this review, we discuss cfDNA in patients with RA, particularly the sources of cfDNA and the correlation of cfDNA with RA pathogenesis. We also highlight the potential of analyzing cfDNA profiles to guide individualized treatment approaches for RA.
MDPI AG, 2021年08月19日, International Journal of Molecular Sciences, 22 (16), 8941 - 8941, 英語[査読有り]
研究論文（学術雑誌）
OBJECTIVE: Diurnal variation of symptoms are observed in rheumatoid arthritis, especially in productions of cytokines that show peak concentrations during mid night. In contrast, cytokines of collagen-induced arthritis (CIA) mice increase in daytimes under Mid-light condition. By using chronotherapy, differences in drug efficacies according to administration time of Baricitinib, a wide ranged cytokine blocker, were examined in CIA mice. METHODS: CIA mice were administered a dose of 3 mg/kg of Baricitinib once a day at zeitgeber time (ZT) 0 or ZT12 for 21 days. Arthritis scores, histopathology and factors related to joint destruction in sera were examined. Phosphorylation of STAT3 in liver, expressions of cytokines in spleen, and Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in sera were measured. RESULTS: In CIA mice, diurnal variations were observed both in expressions of cytokines and phosphorylation of STAT3. Arthritis scores of ZT0/12 group decreased from day3 as compared to untreated mice, and those of ZT0 group significantly decreased as compared to ZT12 group from day12. Pathological findings, immunohistochemistry of cytokines and Receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin ratio in sera well reflected results of arthritis scores. Diurnal variation of STAT3 phosphorylation was suppressed in ZT0 group. At ZT2, expressions of IL-6/Interferon-γ/TNF/granulocyte-macrophage colony-stimulating factor in ZT0 group were significantly decreased as compared to untreated mice, though not in ZT12 group. In ZT0 group, IL-6 and TNF-α in sera were decreased for longer time than that in ZT12 group. CONCLUSION: Chronotherapy using Baricitinib targeting cytokine secretions is effective in CIA mice. Clinical applications of chronotherapy can be expected to enhance the drug efficacy.
2020年07月, International immunopharmacology, 84, 106549 - 106549, 英語, 国際誌[査読有り]
研究論文（学術雑誌）
- 2019年09月, Scandinavian Journal of Rheumatology, 48 (5), 353 - 361, 英語Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators and proliferate rheumatoid arthritis fibroblast-like synovial cells.
[査読有り]
研究論文（学術雑誌）
Objectives: Rheumatoid Arthritis (RA) is the autoimmune disease representing the circadian variations of symptoms such as morning stiffness of joints or increased production of cytokines around midnight. Clock genes have been reported to affect on the pathogenesis of RA, however, the detailed relation between clock genes and disease activities of RA has remained unclear.Methods: In this study, 15 RA patients treated with biological disease modifying anti-rheumatic drugs (bDMARDs) were enrolled (TNF inhibitor, 5; IL-6 inhibitor, 5; CTLA4-IgG, 5). Blood samples were collected from RA patients before treatment and at the study end-point fulfilling DAS28-ESR < 3.2. Total RNA was extracted from leukocytes to examine the expressions of the clock genes. We then evaluated the correlation of the clock gene expression with disease activity and the diagnostic values of the clock genes.Results: The expressions of the clock genes were significantly modulated by bDMARDs treatments. Disease activities were significantly correlated with the clock genes expressions, and disease remission/low disease activity could be distinguished from moderate/high disease activity due to the sensitivities, the specificities and the areas under the curves of that.Conclusion: The expressions of the clock genes in leukocytes could be useful as novel biomarkers predicting disease activities and therapeutic efficacies for bDMARDs in RA treatments.
2019年05月, Modern Rheumatology, 30 (2), 293 - 300, 英語, 国際誌[査読有り]
研究論文（学術雑誌）
To determine whether the short-term assessment of pulse rate variability (PRV) is a surrogate for that of heart rate variability (HRV) in an elderly population under resting conditions, we collected photoplethysmography (PPG) and electrocardiography (ECG) signals simultaneously, and analyzed their association and agreement with HRV and PRV components. We divided the elderly population into three groups, namely, those younger than 70 years (< 70 yrs), those older than 70 years and younger than 80 years (70–79 yrs), and those older than 80 years (≥ 80 yrs), and we found that PRV was more underestimated than HRV with increasing age, although the PRV components highly correlated with the HRV components in the three groups. Thus, PRV can be used to examine the autonomic nervous system (ANS) function in elderly populations. However, the interpretation of results should consider the effect of aging, particularly in those older than 80 years.
(一社)日本臨床衛生検査技師会, 2018年05月, Japanese Journal of Medical Technology, 67 (3), 289 - 293, 英語, 国内誌[査読有り]
研究論文（学術雑誌）
Background: Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts. Methods: Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction. Protein expression of circadian clock gene PERIOD2 (PER2) and CYTOCHROME C was also examined by western blotting and ELISA. Promoter activities of Per2 and Bik were measured by Luciferase assay. Expression of PER2, BIK, and CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. Synovial fibroblasts were transfected with Per2/Bik small interfering RNA, and successively treated with MTX to determine cell viabilities. Finally, synovial fibroblasts were treated with MTX according to the oscillation of Per2/Bik expression. Results: MTX (10 nM) significantly decreased cell viabilities, but increased messenger RNA expression of Per2, Bik, and PAR ZIP including D site of the albumin promoter binding protein (Dbp), hepatic leukemia factor (Hlf), and thyrotroph embryonic factor (Tef). MTX also increased protein expression of PER2 and CYTOCHROME C, and promoter activities of Per2 and Bik via D-box. Under fluorescent observations, expression of PER2, BIK, and CYTOCHROME C was increased in apoptotic cells. Cytotoxicity of MTX was attenuated by silencing of Per2 and/or Bik, and revealed that MTX was significantly effective in situations where Per2/Bik expression was high. Conclusions: We present here novel unique action of MTX on synovial fibroblasts that upregulates PAR bZIP to transcribe Per2 and Bik, resulting in apoptosis induction. MTX is important in modulating circadian environments to understand a new aspect of pathogenesis of RA.
BioMed Central Ltd., 2018年03月22日, Arthritis Research and Therapy, 20 (1), 55 - 55, 英語[査読有り]
研究論文（学術雑誌）
Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca2+ chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α. Oscillation phase and amplitude of Bmal1, transcriptional activator Rorα, transcriptional repressor Rev-erbα, and histone acetyltransferases (p300 and Cbp) were evaluated by quantitative real-time PCR. As results, TNF-α did not influence the oscillation phase of Rev-erbα, while enhanced those of Rorα, resulting in over-expression of Bmal1. When Ca2+ influx was inhibited by BAPTA-AM, TNF-α-mediated up-regulation of Rorα was cancelled, however, that of Bmal1 was still apparent. When we further explored another pathway between TNF-α and Bmal1, TNF-α suppressed the expression of Rev-erbα in the absence of Ca2+ influx, as well as those of p300 and Cbp genes. Finally, actions of TNF-α, in increasing Bmal1/Rorα and decreasing Rev-erbα, were cancelled by C646 treatment or silencing of both p300 and Cbp. In conclusion, we determined a novel role of TNF-α in inducing Bmal1 via dual calcium dependent pathways Rorα was up-regulated in the presence of Ca2+ influx and Rev-erbα was down-regulated in the absence of that. Results proposed that inhibition of p300/CBP could be new therapeutic targets for RA.
Elsevier B.V., 2018年01月08日, Biochemical and Biophysical Research Communications, 495 (2), 1675 - 1680, 英語[査読有り]
研究論文（学術雑誌）
- 2018年, Journal of Translational Science, 4 (4), 1, 英語
[査読有り]
研究論文（学術雑誌）
Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology. To unravel the molecular mechanisms in RA, we performed targeted DNA sequencing analysis of patients with RA. This analysis identified a variant of the death receptor 3 (DR3) gene, a member of the family of apoptosis-inducing Fas genes, which contains four single-nucleotide polymorphisms (SNPs) and a 14-nucleotide deletion within exon 5 and intron 5. We found that the deletion causes the binding of splicing regulatory proteins to DR3 pre-mRNA intron 5, resulting in a portion of intron 5 becoming part of the coding sequence, thereby generating a premature stop codon. We also found that this truncated DR3 protein product lacks the death domain and forms a heterotrimer complex with wildtype DR3 that dominant-negatively inhibits ligand-induced apoptosis in lymphocytes. Myelocytes from transgenic mice expressing the human DR3 variant produced soluble truncated DR3, forming a complex with TNF-like ligand 1A (TL1A), which inhibited apoptosis induction. In summary, our results reveal that a DR3 splice variant that interferes with ligand-induced T cell responses and apoptosis may contribute to RA pathogenesis.
American Society for Biochemistry and Molecular Biology Inc., 2018年, Journal of Biological Chemistry, 293 (6), 1933 - 1943, 英語[査読有り]
研究論文（学術雑誌）
Aim: To evaluate the correlation between circulating cell-free DNA (ccfDNA) in plasma and clinical disease activities in patients with rheumatoid arthritis (RA). Method: The study group included 30 patients with RA who started biological disease-modifying anti-rheumatic drugs (DMARDs) therapy. The concentration of ccfDNA in plasma was measured by quantitative real-time polymerase chain reaction at baseline to 24 weeks in every 4-week period from 30 patients and 21 healthy individuals. We also evaluated the correlation between ccfDNA and the clinical activity or the therapeutic response for biological DMARDs, using the simplified disease activity index (SDAI), Disease Activity Score of 28 joints (erythrocyte sedimentation rate) and the European League Against Rheumatism (EULAR) response criteria. Synovial fluid samples of knee joints were collected from 13 patients with RA and 12 with osteoarthritis (OA) to measure ccfDNA. Result: The concentration of ccfDNA in RA patients at baseline was higher than healthy controls (P = 0.016). After introducing biological DMARDs, ccfDNA was increased until 8 weeks from the baseline, and decreased after 12 weeks. The average of SDAI was improved in all patients enrolled. At 12 weeks after treatment, 15 patients were good responders to the EULAR response criteria, nine showed moderate response and six showed no response. ccfDNA in good responders was increased until 8 weeks, while those of moderate or no response were not (P = 0.042). In joint fluid of RA patients, ccfDNA was remarkably increased as compared to those from OA (P = 0.00011). Conclusion: After introducing biological DMARDs, increase of ccfDNA at 8 weeks was associated with improvement of disease activities. Compared with biomarkers reported, ccfDNA is able to predict the early therapeutic effects of biological DMARDs in RA patients.
WILEY, 2017年06月, INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, 20 (6), 722 - 730, 英語[査読有り]
研究論文（学術雑誌）
- 2015年, International Journal of Clinical Rheumatology, 10 (5), 335 - 344, 英語
[査読有り]
研究論文（学術雑誌）
Among the symptoms of patients with rheumatoid arthritis ( RA), joint stiffness is influenced by diurnal rhythm and reaches peak in the morning, which is a common complaint and reflects the circadian nature of disease manifestation. In addition, inflammatory cytokines, which reach peak secretion early in the morning are major players causing the morning stiffness. In this review, we explore the link between the circadian clock and inflammation, focusing on the interactions of various clock genes with the immune-pathways underlying the pathology of rheumatoid arthritis.
HINDAWI PUBLISHING CORPORATION, 2014年, JOURNAL OF IMMUNOLOGY RESEARCH, 2014, 282495, 英語[査読有り]
研究論文（学術雑誌）
Characteristic features of rheumatoid arthritis (RA) include the production of proinflammatory cytokines and disease-specific auto-antibodies and the manifestation of disease symptoms in a circadian pattern, typified by morning stiffness. The pathogenesis of RA involves the activation of the proto-oncogene c-Fos and the cell cycle regulator Wee1 kinase, which cause synovial cellular overgrowth leading to characteristic 'tumor-like' and arthritic joint destruction. It has been reported that in mice genetically deleted for cryptochrome (Cry) 1/2, circadian clock genes that directly regulate circadian rhythm, free-running rhythmicity is abolished and Wee1 kinase is constitutively upregulated. Therefore, to examine more closely the potential circadian regulation of rheumatoid arthritis, we induced experimental arthritis in Cry knockout mice and observed an interplay between Cry gene activity and proinflammatory cytokine tumor necrosis factor-α (TNF-α) production. Thus, the biological clock and arthritis influence each other, and a further understanding of this interplay could lead to treatments that may improve the activity of daily living (ADL) of patients with RA. © 2013-IOS Press and the authors. All rights reserved.
2013年, Advances in Neuroimmune Biology, 4 (1), 7 - 11, 英語[査読有り]
研究論文（学術雑誌）
Objectives: To study the effect of tumour necrosis factor (TNF)-α, responsible for the inflammation and circadian rhythm of rheumatoid arthritis (RA), on the expression of circadian clock genes in primary cultured human rheumatoid synovial cells. Method: The expression of circadian clock genes, including circadian locomotor output cycles kaput (Clock), brain and muscle Arnt-like protein-1 (Bmal1), period (Per)1/2, and cryptochrome (Cry)1/2, and the proline and acidic amino acid-rich basic leucine zipper (PAR bZip) genes, a transcriptional activator of Per2, including D site of albumin promoter binding protein (Dbp), hepatic leukaemia factor (Hlf), and thyrotroph embryonic factor (Tef), and a transcriptional repressor of Per2, E4-binding protein 4 (E4bp4), in TNF-α-stimulated synovial cells was determined by real-time polymerase chain reaction (PCR). The D-box motifs in the Per2 promoter were mutated by site-directed mutagenesis, and the promoter activity of the Per2 gene was examined using the luciferase assay. Results: TNF-α enhanced the mRNA expression of Bmal1 and Cry1 but did not affect that of Clock, Per1, or Cry2. However, TNF-α inhibited the mRNA expression of the Per2 gene, as well as Dbp, Hlf, and Tef, but enhanced the mRNA expression of E4bp4. Furthermore, TNF-α inhibited the transcriptional activity of the wild-type Per2 gene in a manner dependent on the D-box 1 and D-box 2 motifs in the Per2 promoter. Conclusions: TNF-α modulates the expression of the Per2 gene through the D-box binding proteins DBP, HLF, TEF, and E4BP4, in rheumatoid synovial cells, and thereby may contribute to the pathogenesis of RA. © 2013 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation.
2013年, Scandinavian journal of rheumatology, 42 (4), 276 - 280, 英語[査読有り]
研究論文（学術雑誌）
- WILEY-BLACKWELL, 2013年01月, TISSUE ANTIGENS, 81 (1), 44 - 45, 英語
[査読有り]
研究論文（学術雑誌）
Objective. To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE). Methods. Japanese patients with SLE (n = 716), those with rheumatoid arthritis (RA) (n = 327), and healthy control subjects (n = 351) were genotyped for the Val(129)Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene. Recombinant human MICA-GST fusion proteins were tested on the NK cell line NK92MI for the expression of NK group 2, member D (NKG2-D), NK cell-mediated cytotoxicity, and interferon-gamma (IFN gamma) production. Results. The MICA (129)Met allele, TMA9 allele, and (129)Met/Met genotype were positively associated with SLE (corrected P [P-corr] = 0.01 and odds ratio [OR] 1.3, P-corr = 0.003 and OR 1.6, and P-corr = 0.02 and OR 1.8, respectively), while the MICA (129)Val allele was negatively associated with SLE (P-corr = 0.01, OR 0.8). The MICA (129)Met;A9 haplotype was also associated with SLE (P-corr = 0.0006, OR 1.8), and there was an additive genetic effect between the MICA (129)Met; A9 haplotype and HLA-DRB1*15:01. When NK92MI cells were incubated in vitro with recombinant human disease-associated (129)Met; A9 (the combination of polymorphisms at (129)Met and TMA9), expression of NKG2-D on NK92MI cells and cytotoxicity of the NK cells were inhibited, but production of IFN gamma from NK92MI cells was enhanced. Conclusion. The MICA polymorphism is genetically associated with SLE, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function.
WILEY-BLACKWELL, 2011年10月, ARTHRITIS AND RHEUMATISM, 63 (10), 3058 - 3066, 英語[査読有り]
研究論文（学術雑誌）
Methods. Expression of integrin-alpha 5 beta 1 and integrin-linked kinase (ILK) in synovial cells was determined by western blot. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with particularly interesting new cysteine-histidine protein (PINCH) and alpha-parvin, and activation of Rac/cdc42 in synovial cells were examined by using immunohistochemistry and immunoprecipitation. Apoptosis induction by GA treatment was analysed by nuclear staining, cell proliferation assay and western blot of caspase. Effects of GA on mitogen-activated protein kinase (MAPK), PI-3K/protein kinase B (Akt) pathway, mitochondrial Bcl-2 pathway and activation of nuclear factor-kappa B (NF-kappa B) were examined by western blot and ELISA. Results. HSP90 was overexpressed in synovial cells while GA decreased the expression of integrin-alpha 5 beta 1 and ILK. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with PINCH and alpha-parvin, and activation of Rac/cdc42 in synovial cells were all inhibited by GA treatment. We found that HSP90 stabilized and regulated the MAPK and PI-3K/Akt pathway, thereby inhibiting HSP90-potentiated synovial apoptosis by stimulating caspases and the mitochondrial Bcl-2 pathway on the one hand and inhibiting the activation of NF-kappa B on the other. Conclusion. The contribution of HSP90 is important in the pathogenesis of RA that potentiates a tumour-like synovial overgrowth by stabilizing ILK, extracellular signal-regulated kinase and Akt.
OXFORD UNIV PRESS, 2011年05月, RHEUMATOLOGY, 50 (5), 852 - 861, 英語[査読有り]
研究論文（学術雑誌）
Synovial mesenchymal cells, matrix metalloproteinases (MMPs), and osteoclasts are the three major players directly responsible for the pathogenesis of rheumatoid joint destruction. First, synovial mesenchymal cells, internally driven by a transcription factor c-Fos/AP-1, not only directly invade cartilage and bone as a granulation tissue called "pannus" but also release inflammatory cytokine interleukin (IL)-1 beta. IL-1 beta induces MMPs and activates osteoclasts. Synovial cells can also present antigen to T cells to drive antigen-specific immune responses. Second, cartilaginous joint matrix can only be degraded after the first attack of collagen fibrils by MMPs, and importantly, most of the MMPs are under the control of c-Fos/AP-1 and IL-1 beta as well. Third, differentiation of osteoclast is driven internally by NFATc1, where NFATc1 is under the control of TRAF6, c-Fos/AP-1 and osteoclastogenic signaling complex. IL-1 beta has been shown to induce osteoclastogenesis directly and also indirectly via signaling through RANKL. Therefore, IL-1 beta and c-Fos/AP-1 influence each other's gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, and thus, blockade of IL-1 beta and/or c-Fos/AP-1 can be most promising as a therapeutic target, and in fact, a selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction.
SPRINGER BASEL AG, 2011年04月, ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, 59 (2), 89 - 95, 英語[査読有り]
研究論文（学術雑誌）
The mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm. We show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are disturbed in mouse models of experimental arthritis. Expressions of other clock genes, Bmall and Dbp, are also disturbed in spleen cells by arthritis induction. Deletion of Cry1 and Cry2 results in an increase in the number of activated CD3(+) CD69(+) T cells and a higher production of TNF-alpha from spleen cells. When arthritis is induced, Cry1(-/-)Cry2(-/-) mice develop maximal exacerbation of joint swelling, and upregulation of essential mediators of arthritis, including TNF-alpha, IL-1 beta and IL-6, and matrix metalloproteinase-3. Wee-1 kinase is solely upregulated in Cry1(-/-)Cry2(-/-) mice, in line with upregulation of c-Fos and Wee-1 kinase in human rheumatoid arthritis. The treatment with anti-TNF-alpha Ab significantly reduced the severity and halted the progression of the arthritis of Cry1(-/-)Cry2(-/-) mice and vice versa, ectopic expression of Cry1 in the mouse embryonic fibroblast from Cry1(-/-)Cry2(-/-) mice significantly reduced the trans activation of TNF-a gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease. The Journal of Immunology, 2010, 184: 1560-1565.
AMER ASSOC IMMUNOLOGISTS, 2010年02月, JOURNAL OF IMMUNOLOGY, 184 (3), 1560 - 1565, 英語[査読有り]
研究論文（学術雑誌）
Objective. To determine whether angiopoietin 1 (Ang-1) potentiates overgrowth of the synovium and joint degradation in rheumatoid arthritis (RA), and to clarify the cell-signaling mechanisms of Ang-1 in the rheumatoid joint. Methods. Expression of Ang-1, TIE-2 (a receptor for Ang-1), and matrix metalloproteinase 3 (MMP-3) was studied by immunohistochemistry. Activation of the ERK/MAPK and phosphatidylinositol (PI) 3-kinase/Akt pathways and of NF-kappa B was determined by Western blotting and an NF-kappa B p65 DNA binding activity assay, respectively. Induction of apoptosis was evaluated by nuclear staining, cell viability assay, and Western blotting of caspases. Synovial cell migration was evaluated by actin polymerization, Western blotting of Rho family proteins, and affinity purification with Rhotekin-Rho and p21-activated kinase 1. Matrix degradation was examined by induction of proMMP-3 secretion from synovial cells followed by in vitro cartilaginous matrix degradation assay. Results. Ang-1 stimulated the ERK/MAPK and PI 3-kinase/Akt pathways in a cooperative but independent manner, which enhanced rheumatoid synovium overgrowth and joint destruction. In addition, Ang-1 activated NF-kappa B via Akt to promote cell growth, but also inhibited cell apoptosis via ERK and Akt. Ang-1 directly potentiated the extension of synovial cells in an ERK-and Akt-dependent manner by up-regulating Rho family proteins, which attenuated Rac signaling and led to membrane ruffling. Ang-1 induced proMMP-3 secretion from synovial cells, which resulted in direct degradation of the cartilaginous matrix. Conclusion. Ang-1 stimulates the ERK/MAPK and PI 3-kinase/Akt pathways cooperatively, but in a manner independent of each other, to directly potentiate synovium overgrowth and joint destruction in RA. In addition to inflammatory cytokines, Ang-1/TIE-2 signaling appears to be an independent factor that contributes to the destruction of the rheumatoid joint.
WILEY-LISS, 2007年07月, ARTHRITIS AND RHEUMATISM, 56 (7), 2170 - 2179, 英語[査読有り]
研究論文（学術雑誌）
MISC
- 2022年04月, 医学のあゆみ, 281 (2), 180 - 185体内時計による関節リウマチの制御
- (一社)日本リウマチ学会, 2021年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 65回, 546 - 546, 日本語時計制御遺伝子Tefは細胞周期調節因子を介してRA滑膜細胞の増殖を制御する
- (一社)日本リウマチ学会, 2021年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 65回, 547 - 547, 日本語IL-6は時計遺伝子PAR-bZIPを介して関節リウマチ滑膜細胞に細胞死抵抗性をもたらす
- (一社)日本リウマチ学会, 2021年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 65回, 548 - 548, 日本語時計遺伝子Bmal1を介したRA滑膜細胞の炎症性メディエーター産生
- (一社)日本リウマチ学会, 2020年08月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64回, 551 - 551, 日本語TNFα誘導性CCL2は転写因子RORα/REV-ERBα、ヒストンアセチル化酵素CBP/p300を介してRA滑膜細胞の遊走に関与する
- (一社)日本リウマチ学会, 2020年08月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64回, 649 - 649, 日本語JAK阻害剤Baricitinibを用いた薬物時間療法はマウス関節炎を効果的に抑制する
- (一社)日本リウマチ学会, 2020年08月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64回, 705 - 705, 日本語IL-6はミトコンドリア内因性経路を介して関節リウマチ滑膜細胞に細胞死抵抗性をもたらす
- (一社)日本リウマチ学会, 2020年08月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64回, 706 - 706, 日本語IL-6、TNF-α刺激によるRA滑膜細胞の増殖は時計制御遺伝子Tefによって制御される
- WILEY, 2019年10月, ARTHRITIS & RHEUMATOLOGY, 71, 英語Roles of Histone Acetyltransferases CBP/p300 and Transcriptional Factor ROR alpha/REV-ERB alpha Against TNF alpha-induced CCL2 Expression in RA-FLSs
研究発表ペーパー・要旨（国際会議）
- WILEY, 2019年10月, ARTHRITIS & RHEUMATOLOGY, 71, 英語Chronotherapy Using Baricitinib Attenuates Collagen-induced Arthritis in Mice
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2019年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 63回, 446 - 446, 日本語リウマチ性疾患の基礎研究-1 関節リウマチモデルマウスにおけるJAK阻害剤を用いた時間治療の検討
- (一社)日本リウマチ学会, 2019年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 63回, 489 - 489, 日本語関節リウマチの治療評価と予測-2 生物学的製剤治療が関節リウマチ患者白血球における時計遺伝子発現を変動させる
- (一社)日本リウマチ学会, 2019年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 63回, 603 - 603, 日本語滑膜細胞におけるTNFα誘導性CCL2発現増加に対するヒストンアセチル化酵素と転写因子RORα/REV-ERBαの役割
- (一社)日本リウマチ学会, 2019年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 63回, 604 - 604, 日本語IL-6は時計遺伝子Hlfを介して関節リウマチ滑膜細胞に細胞死抵抗性をもたらす
- (一社)日本リウマチ学会, 2018年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 539 - 539, 日本語リウマチ性疾患の基礎研究2 IL-6とTNFαは細胞周期調節因子を介して協調的に滑膜細胞増殖に関与する
- (一社)日本リウマチ学会, 2018年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 706 - 706, 日本語TNF-αはc-Mycを介してリウマチ滑膜細胞のp27Kip発現を変化させる
- (一社)日本リウマチ学会, 2018年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 779 - 779, 日本語時計遺伝子Bmal1は細胞周期調節因子を介して関節リウマチ滑膜細胞の増殖能を制御する
- (一社)日本リウマチ学会, 2018年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 782 - 782, 日本語IL-6は時計遺伝子を介して滑膜細胞に細胞死抵抗性をもたらす
- WILEY, 2017年10月, ARTHRITIS & RHEUMATOLOGY, 69, 英語IL-6 and TNF-a Cooperate to Modulate the Cell Cycle of RA-Fibroblast-like Synoviocytes Via Cyclin Dependent Kinase Inhibitors
研究発表ペーパー・要旨（国際会議）
- BMJ PUBLISHING GROUP, 2017年06月, ANNALS OF THE RHEUMATIC DISEASES, 76, 499 - 499, 英語
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2017年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61回, 589 - 589, 日本語リウマチ性疾患の基礎研究/サイトカイン・ケモカイン 転写因子群PAR bZIPを介したメトトレキサートの新しい薬理作用
- (一社)日本リウマチ学会, 2017年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61回, 711 - 711, 日本語時計遺伝子が滑膜細胞の細胞周期を調節する
- (一社)日本リウマチ学会, 2017年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61回, 712 - 712, 日本語IL-6とTNF-αが関節リウマチ滑膜細胞の細胞周期調節因子の発現を制御する
- (一社)日本リウマチ学会, 2017年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61回, 713 - 713, 日本語TNFαはヒストンアセチル化酵素を介してRA滑膜細胞内の時計遺伝子Bmal1発現を調節する
- (一社)日本リウマチ学会, 2017年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61回, 804 - 804, 日本語DNA integrity indexを用いたTCZの新しい薬理効果の検証
- WILEY, 2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語TCZ Modulates the Production of Ccfdna Derived from RA Synovial Cells
研究発表ペーパー・要旨（国際会議）
- WILEY, 2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語IL-6 and TNF-alpha Modulate Expressions of Cell Cycle Regulators of Rheumatoid Arthritis Fibroblast-like Synoviocytes
研究発表ペーパー・要旨（国際会議）
- WILEY, 2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語A Novel Pharmacological Action of MTX on RA Fibroblast-like Synoviocytes Via Circadian Clock Genes
研究発表ペーパー・要旨（国際会議）
- BMJ PUBLISHING GROUP, 2016年06月, ANNALS OF THE RHEUMATIC DISEASES, 75, 983 - 983, 英語
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2016年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60回, 334 - 334, 日本語関節リウマチの治療 バイオマーカー RA滑膜細胞由来の遊離DNA産生はTCZにより制御される
- (一社)日本リウマチ学会, 2016年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60回, 449 - 449, 日本語関節リウマチの治療評価と予測 関節リウマチ患者における血清遊離DNAの臨床的意義
- (一社)日本リウマチ学会, 2016年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60回, 492 - 492, 日本語Ca2+イオンによる時計遺伝子発現リズムの制御
- (一社)日本リウマチ学会, 2016年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60回, 492 - 492, 日本語メトトレキサートがRA-FLSの時計遺伝子に与える影響
- (一社)日本リウマチ学会, 2015年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 59回, 337 - 337, 日本語リウマチ性疾患の基礎研究 IL-6は転写調節因子RORαに作用してRA滑膜細胞の時計遺伝子発現を調節する
- (一社)日本リウマチ学会, 2015年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 59回, 471 - 471, 日本語Calcium signal伝達系を介したTNF-αによる時計遺伝子発現制御
- (一社)日本リウマチ学会, 2015年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 59回, 484 - 484, 日本語トシリズマブ治療によるRA患者血清ccf-DNA量の変化と疾患活動性の相関
- WILEY-BLACKWELL, 2014年10月, ARTHRITIS & RHEUMATOLOGY, 66, S457 - S458, 英語TNF-a Modulates the Expression of Circadian Clock Genes Via Calcium Signaling in Rheumatoid Synovial Cells
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2014年03月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 58回, 661 - 661, 日本語IL-6シグナルは関節リウマチ患者滑膜細胞の時計遺伝子発現を変化させる
- (一社)日本リウマチ学会, 2013年03月, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 57回・22回, 555 - 555, 日本語TNFαは関節リウマチ滑膜細胞の時計遺伝子Per2発現量をD-box配列を介して抑制する
- WILEY-BLACKWELL, 2012年10月, ARTHRITIS AND RHEUMATISM, 64 (10), S186 - S186, 英語TNF alpha Modulates the Expression of Circadian Clock Gene, Per2, Via D-Box Motif in the Promoter Region in Rheumatoid Synovial Cells.
[査読有り]
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2012年03月19日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 56th-21st, 486 - 486, 日本語TNFαが関節リウマチ患者滑膜細胞の時計遺伝子に及ぼす影響
- WILEY, 2011年10月, ARTHRITIS AND RHEUMATISM, 63 (10), S141 - S142, 英語TNF alpha Modulates the Expression of Circadian Clock Genes in Rheumatoid Synovial Cells.
[査読有り]
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2011年06月20日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 55th-20th, 471 - 471, 日本語TNFaは関節リウマチ患者滑膜細胞の時計遺伝子発現を変化させる
- (一社)日本リウマチ学会, 2011年06月20日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 55th-20th, 490 - 490, 日本語スプライシング調節蛋白質が変異型ヒトDR3遺伝子のイントロン5に結合する
- (一社)日本リウマチ学会, 2011年06月20日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 55th-20th, 283 - 283, 日本語MICA 129ValアリルはHLA‐DRB1と独立した日本人MCTD患者における遺伝素因である
- 2010年11月, ARTHRITIS AND RHEUMATISM, 62Identification of a pathological TCR of autoantibody-inducing CD4+ T cell that induces autoantibodies and lupus-like immune tissue injury
[査読有り]
- 体内時計と身近な病気 時計遺伝子と関節リウマチ
関節リウマチは原因不明の多関節炎であるが、「朝のこわばり」に象徴される病状の日内変動が特徴のひとつである。私達は関節リウマチの病態を解析する過程で、原癌遺伝子c-fosと細胞周期調節因子Wee-1キナーゼの活性化が、関節滑膜細胞の腫瘍性増殖の一因であることを見出した。一方、時計遺伝子Cryノックアウトマウスでは全身の体内時計が停止するとともにWee-1キナーゼの著明な発現亢進が報告され、私達は、Cryノックアウトマウスを用いたモデル関節炎を作成し、時計遺伝子と関節炎の関与を検討した。その結果、Cry遺伝子と炎症性サイトカインTNF-αの相互調節作用が明らかになり、日内リズム異常と炎症性関節炎の新たな関係性が示唆された。(著者抄録)
(株)金芳堂, 2010年10月20日, 脳21, 13 (4), 390-395,366 - 395, 日本語 - (一社)日本リウマチ学会, 2010年03月19日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 54th-19th, 533 - 533, 日本語関節リウマチの疾患遺伝子変異型DR3のイントロン5にスプライシング調節蛋白が結合する
- (一社)日本リウマチ学会, 2010年03月19日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 54th-19th, 453 - 453, 日本語MICA129Met/A9アレルはSLEに強く関与する
- 2009年03月19日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 53rd-18th, 213, 日本語変異型MICAはNK細胞のIFNγ産生を強く誘導する
- 2009年03月19日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 53rd-18th, 374, 日本語抗TNFα抗体はCry欠損マウスの実験的関節炎を抑制する
- 2009年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 53rd-18thNK細胞からのIFNγ産生が亢進している変異MICAと野生型MICAの比較
- 一般社団法人 日本臨床リウマチ学会, 2009年, 臨床リウマチ, 21 (4), 425 - 426, 日本語
- 2008年09月, ARTHRITIS AND RHEUMATISM, 58 (9), S515Arthritis modulates biological clock: Cry directly regulates the transactivation, of TNF-alpha gene
[査読有り]
- 2008年09月, ARTHRITIS AND RHEUMATISM, 58 (9), S657Hsp 90 modulates actin filament rearrangement in rheumatoid synovial cell via IIk-dependent pathway
[査読有り]
- 2008年09月, ARTHRITIS AND RHEUMATISM, 58 (9), S815Genetic polymorphism of MHC class I chain-related gene A (MICA) in Japanese patients with systemic lupus erythematosus (SLE)
[査読有り]
- (一社)日本リウマチ学会, 2008年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 52nd-17th, 253 - 253, 日本語実験的関節炎誘導による概日リズムの障害
- (一社)日本リウマチ学会, 2008年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 52nd-17th, 253 - 253, 日本語時計遺伝子欠損マウスにおける実験的関節炎の増悪には炎症性サイトカインTNFαが関与する
- (一社)日本リウマチ学会, 2008年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 52nd-17th, 254 - 254, 日本語時計遺伝子CryとNKG2Dレセプター/NKG2Dリガンド相互作用
- (一社)日本リウマチ学会, 2008年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 52nd-17th, 308 - 308, 日本語MICA遺伝子多型によるSLE,RA疾患感受性の検討
- B M J PUBLISHING GROUP, 2007年07月, ANNALS OF THE RHEUMATIC DISEASES, 66, 138 - 139, 英語Association of major histocompatibility complex class I chain-related gene A (MICA) A4/A5.1 and A5/A5.1 genotypes with Japanese patients with rheumatoid arthritis (RA)
[査読有り]
研究発表ペーパー・要旨（国際会議）
- (一社)日本リウマチ学会, 2007年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 51st-16th, 369 - 369, 日本語日本人関節リウマチ患者におけるMICA遺伝子多型解析
- (一社)日本リウマチ学会, 2007年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 51st-16th, 414 - 414, 日本語Heat schock protein 90はインテグリンを介して関節リウマチ滑膜細胞のシグナル伝達に作用する
- 2007年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 51st-16th, 369, 日本語日本人関節リウマチ患者におけるMICA遺伝子多型解析
- (一社)日本リウマチ学会, 2007年, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 51st-16th, 263 - 263, 日本語Angiopoietin‐1は滑膜細胞上のVLA‐5(α5β1インテグリン)を介してシグナル伝達する
- (一社)日本リウマチ学会, 2006年03月23日, 日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集, 50th-15th, 193 - 193, 日本語滑膜細胞内シグナル伝達におけるAngiopoietin‐1とα5β1インテグリンの相互作用
所属学協会
共同研究・競争的資金等の研究課題
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2023年04月01日 - 2026年03月31日認知症における新規血中バイオマーカーの探索 ～炎症誘導性マイクロRNAの意義～
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2022年04月01日 - 2025年03月31日Tef 遺伝子改変マウスを用いた関節リウマチ病態解析と創薬へのアプローチ
- 公益財団法人 ひょうご科学技術協会, 令和5年度学術研究助成, 2023年04月 - 2024年03月認知症における新規血中バイオマーカーの探索～炎症誘導性マイクロRNAの意義～
- 黒住医学研究振興財団, 2021年度「第29回研究助成金」, 2021年10月血清カリウム値が冷蔵保管で増加する原因 ～血球層が「分離剤を超えて」血清層へ混入～
- 日本学術振興会, 科学研究費補助金（若手研究B), 2017年04月 - 2020年03月, 研究代表者
競争的資金
- 日本学術振興会, 科学研究費補助金（若手研究B), 2014年04月 - 2016年03月, 研究代表者
競争的資金