scholarly journals Blockade of translationally controlled tumor protein attenuated the aggressiveness of fibroblast-like synoviocytes and ameliorated collagen-induced arthritis

2021 ◽  
Author(s):  
Mingyo Kim ◽  
Yongho Choe ◽  
Heewon Lee ◽  
Min-Gyu Jeon ◽  
Jin-Ho Park ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Inflammatory Responses ◽  
Joint Destruction ◽  
Serum Levels ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Translationally Controlled Tumor Protein ◽  
Tuberculosis Model ◽  
Biochemical Analyses ◽  
Fibroblast Like Synoviocytes

AbstractHistamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.

scholarly journals SAT0007 BLOCKING HISTAMINE-RELEASING FACTOR/TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (HRF/TCTP) ATTENUATES AGGRESSIVENESS OF FIBROBLAST-LIKE SYNOVIOCYTES AND AMELIORATES COLLAGEN-INDUCED ARTHRITIS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 934.3-934
Author(s):  
M. Kim ◽  
Y. Choe ◽  
H. Lee ◽  
Y. H. Cheon ◽  
S. I. Lee
Keyword(s):  
Rheumatoid Arthritis ◽  
Cancer Progression ◽  
Inflammatory Responses ◽  
Joint Destruction ◽  
Serum Levels ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Translationally Controlled Tumor Protein ◽  
Biochemical Analyses ◽  
Fibroblast Like Synoviocytes

Background:Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses. Increased expression of HRF/TCTP occurs in joints of rheumatoid arthritis (RA) patients, but the role of HRF/TCTP in RA remains undefinedObjectives:In this study, we explored the pathogenic significance of HRF/TCTP and evaluated therapeutic effects of HRF/TCTP blockade in RA.Methods:HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in sera and joint fluids in patients with RA and compared to those with osteoarthritis, ankylosing spondylitis, Behcet disease, and healthy controls. HRF/TCTP expression was also assessed in synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed effects of HRF/TCTP and dimerized HRF/TCTP binding peptide-2 (dTBP2), an inhibitor of HRF/TCTP, in RA-FLS and CIA mice.Results:Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice, and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels were higher in sera, synovial fluid, synovium, and FLS of patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with disease activity in RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effect in a murine tuberculosis model.Conclusion:Our results indicate that HRF/TCTP represents a novel biomarker and therapeutic target for diagnosis and treatment of RA.References:N/AAcknowledgments :National Research Foundation of KoreaKorea Health Industry Development InstituteDisclosure of Interests:None declared

scholarly journals A Novel Spleen Tyrosine Kinase Inhibitor Suppresses Invasiveness of Rheumatoid Arthritis Fibroblast Like Synoviocytes and Improves Collagen Induced Arthritis

2020 ◽  
Author(s):  
Seon Uk Kim ◽  
Hyun Jung Yoo ◽  
Jung Ho Kim ◽  
Hae Jun Hwang ◽  
Jin Kyun Park ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Spleen Tyrosine Kinase ◽  
Collagen Induced Arthritis ◽  
Tnf Α ◽  
Clinical Arthritis ◽  
Syk Inhibitor ◽  
Fibroblast Like Synoviocytes

Abstract Background/PurposeRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by bone and cartilage destruction with leukocyte infiltration and activation at synovial tissue. The fibroblast-like synoviocytes (FLS) have a central role in disease pathogenesis and their invasiveness correlates with articular damage in RA patients. Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase known to have a crucial role in immune receptor signaling. This study aimed to evaluate the inhibitory effect of a novel small-molecule SYK inhibitor, SKI-O-592, on the invasiveness of RA FLS and inflammation of monocytes in vitro and in a mouse collagen-induced arthritis (CIA) model in vivo.MethodsFLS were isolated from synovial tissues of RA patients. FLS were treated with SKI-O-592 for 1 hr and then stimulated with tumor necrosis factor-alpha (TNF-α) for 48 hr. After stimulation, cell viability was measured using cell counting kit-8 (CCK-8) assay. The levels of IL-6, IL-8, CXCL10, MMP-3, and TNF-α were measured in culture supernatant of RA FLS and the monocytic cell line THP-1 cells by ELISA. Wound healing assay transwell migration and invasion assay using RA FLS was performed to evaluate cell migration ability. The adhesion ability of FLS was evaluated by co-culture with calcein-AM labeled THP-1 cells, and the expression of VCAM-1, ICAM-1, α-tubulin, β-actin, total and phosphorylated SYK, c-Jun N-terminal kinase (JNK), p38, ERK, phosphorylated c-Jun, mitogen-activated protein kinase kinase 4 (MKK4), and MKK3/6 was determined by Western blotting. CIA was developed in DBA/1J mice. Clinical arthritis score and histological scores were evaluated after treatment with SKI-O-592.ResultsSKI-O-592 reduced the secretion of chemokine, CXCL10 in RA FLS. Migration of cells to the wound region and through membrane pores and matrigel were decreased by SKI-O-592. Phosphorylation of JNK and p38 was reduced by SKI-O-592 after TNF-α stimulation. SKI-O-592 decreased secretion of TNF-α levels dose-dependently in THP-1 cells with IgG stimulation. The viability and proliferation of FLS and THP-1 were not affected by SKI-O-592. In the CIA model, scores for clinical arthritis and histology were decreased following SKI-O-592 treatment.ConclusionSKI-O-592 inhibited the invasiveness of RA FLS and had an anti-inflammatory effect on monocytes. SKI-O-592 exhibited therapeutic effects in the mouse CIA model by improving clinical and histological scores with amelioration of joint destruction. In conclusion, a novel SYK inhibitor, SKI-O-592, may provide a new therapeutic option for RA patients.

Potent Inhibitory Effects of Quercetin on Inflammatory Responses of Collagen-Induced Arthritis in Mice

2019 ◽  
Vol 19 (3) ◽  
pp. 308-315 ◽  
Author(s):  
Kiichiro Kawaguchi ◽  
Masahiro Kaneko ◽  
Ryo Miyake ◽  
Hiroaki Takimoto ◽  
Yoshio Kumazawa
Keyword(s):  
Oral Administration ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Knee Joints ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Collagen Induced Arthritis ◽  
Tnf Α ◽  
Flavonoid Quercetin

Background: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants. Objective: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice. Methods: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway. Results: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls. Conclusion: These results suggest that oral administration of QUER might effectively improve symptoms of RA.

Arsenic Trioxide Induces Apoptosis of Fibroblast-like Synoviocytes and Represents Antiarthritis Effect in Experimental Model of Rheumatoid Arthritis

2010 ◽  
Vol 38 (1) ◽  
pp. 36-43 ◽  
Author(s):  
YIFANG MEI ◽  
YINING ZHENG ◽  
HUI WANG ◽  
JUAN GAO ◽  
DIANXIN LIU ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mrna Expression ◽  
Arsenic Trioxide ◽  
Messenger Rna ◽  
Caspase 3 ◽  
Joint Destruction ◽  
Flow Cytometric Analysis ◽  
Caspase 8 ◽  
Collagen Induced Arthritis ◽  
Fibroblast Like Synoviocytes

Objective.Recent studies have demonstrated that rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) proliferate as fiercely as tumor cells. Induction of apoptosis in RA FLS therefore provides a new approach for the inhibition of joint destruction. Arsenic trioxide (As2O3) was reported to be an effective apoptosis inducer in a variety of cell types. We investigated the possible effect of As2O3on apoptosis induction of RA FLS and the mechanisms involved in this process.Methods.Apoptosis was determined by flow cytometric analysis, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and transmission electron microscopy. The activity and messenger RNA (mRNA) expression of nuclear factor-κB (NF-κB) was then detected by ELISA and real-time polymerase chain reaction, respectively. Activities of caspase-3 and caspase-8 were evaluated using luminogenic substrates. The effect of As2O3on the morphology of rats with collagen-induced arthritis was evaluated under a light microscope after H&E staining.Results.As2O3significantly enhanced the apoptosis of RA FLS. It suppressed the DNA-binding activity and mRNA expression level of NF-κB, probably by inhibiting tumor necrosis factor-α-induced activation of NF-κB. As2O3treatment significantly increased the activity of both caspase-3 and caspase-8. Morphological analysis revealed histological recovery in the synovial membrane. Synovial hyperplasia and inflammation in the joints were effectively inhibited.Conclusion.As2O3represents an apoptotic effect on RA FLS through NF-κB signaling pathway, and this process is mediated by the activation of caspase cascade. Treatment with As2O3significantly improved the pathologic changes of collagen-induced arthritis and may have potential for treatment of RA.

scholarly journals Aqueous Extract of Kan-Lu-Hsiao-Tu-Tan Ameliorates Collagen-Induced Arthritis in Mice by Inhibiting Oxidative Stress and Inflammatory Responses

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 313
Author(s):  
Chih-Chao Chiang ◽  
Yi-Rong Li ◽  
Kuei-Hung Lai ◽  
Wei-Jen Cheng ◽  
Shih-Chao Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Inflammatory Responses ◽  
Thiobarbituric Acid ◽  
Therapeutic Effects ◽  
Inflammatory Disorder ◽  
Splenocyte Proliferation ◽  
Collagen Induced Arthritis ◽  
Factor Α ◽  
Necrosis Factor

Background: Kan-Lu-Hsiao-Tu-Tan (KLHTT) exhibits anti-psoriatic effects through anti-inflammatory activity in mice. However, the therapeutic effects of KLHTT on rheumatoid arthritis (RA), another significant autoimmune inflammatory disorder, have not been elucidated. Herein, we explored the anti-arthritic effects of KLHTT on collagen-induced arthritis (CIA) in mice. Methods: KLHTT was extracted by boiling water and subjected to spectroscopic analysis. Chicken collagen type II (CII) with complete Freund’s adjuvant was intradermally injected to induce CIA in DBA/1J mice. Anti-CII antibody, cytokines, malondialdehyde (MDA), and hydrogen peroxide (H2O2) were measured using ELISA, thiobarbituric acid reactive substances, and a hydrogen peroxide assay kit. Splenocyte proliferation was tested using thymidine incorporation. Th1 and Th17 cells were analyzed by flow cytometry. Results: Oral KLHTT treatment (50 and 100 mg/kg) ameliorated mouse CIA by decreasing the levels of interleukin (IL)-1β, IL-6, IL-17A, and tumour necrosis factor-α in the paw homogenates and serum. KLHTT also suppressed anti-CII antibody formation, splenocyte proliferation, and splenic Th1 and Th17 cell numbers. Additionally, KLHTT showed antioxidant activity by reducing the concentrations of MDA and H2O2 in paw tissues. Conclusions: The therapeutic effects of KLHTT in CIA mice were through regulating oxidative stress and inflammatory responses. Our results suggest that KLHTT has potential to treat RA.

scholarly journals Aqueous extract of Kan-Lu-Hsiao-Tu-Tan ameliorates collagen-induced arthritis in mice by regulating immune and inflammatory responses

2020 ◽  
Author(s):  
Chih-Chao Chiang ◽  
Yi‐Rong Li ◽  
Kuei-Hung Lai ◽  
Wei-Jen Cheng ◽  
Shih-Chao Lin ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Inflammatory Responses ◽  
Thiobarbituric Acid ◽  
Therapeutic Effects ◽  
Inflammatory Disorder ◽  
Splenocyte Proliferation ◽  
Thiobarbituric Acid Reactive Substances ◽  
Collagen Induced Arthritis ◽  
Factor Α ◽  
Necrosis Factor

Abstract Abstract: Background: Kan-Lu-Hsiao-Tu-Tan (KLHTT) exhibits anti-psoriatic effects through anti-inflammatory activity in mice. However, the therapeutic effects of KLHTT on rheumatoid arthritis (RA), another significant autoimmune inflammatory disorder, are not elucidated. Herein, we explored the anti-arthritic effects of KLHTT on collagen-induced arthritis (CIA) in mice. Methods: KLHTT was extracted by boiling water and subjected to spectroscopic analysis. Chicken collagen type II (CII) with complete Freund’s adjuvant was intradermally injected to induce CIA in DBA/1J mice. Anti-CII antibody, cytokines, malondialdehyde (MDA), and hydrogen peroxide (H2O2) were measured using ELISA, thiobarbituric acid reactive substances, and hydrogen peroxide assay kit. Splenocyte proliferation was tested using thymidine incorporation. Th1 and Th17 cells were analyzed by flow cytometry. Results: Oral KLHTT treatment (50 and 100 mg/kg) ameliorated mouse CIA by decreasing the levels of interleukin (IL)-1β, IL-6, IL-17A, and tumour necrosis factor-α in the paw homogenates and serum. KLHTT also suppressed anti-CII antibody formation, splenocyte proliferation, and splenic Th1 and Th17 cell numbers. Additionally, KLHTT showed antioxidant activity by reducing the concentrations of MDA and H2O2 in paw tissues. Conclusions: The therapeutic effects of KLHTT in CIA mice were through regulating oxidative stress and inflammatory responses. Our results suggest that KLHTT has potential to treat RA.

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