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Blocking translationally controlled tumor protein attenuate aggressiveness of fibroblast-like synoviocytes and ameliorates collagen-induced arthritis
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  • Mingyo Kim,
  • Yongho Choe,
  • Heewon Lee,
  • Min-Gyu Jeon,
  • Jin-Ho Park,
  • Hae Sook Noh,
  • Yun-Hong Cheon,
  • Hee Jin Park,
  • Kyunglim Park,
  • Sung Jae Shin,
  • Kyunglim Lee,
  • Sang-Il Lee
Mingyo Kim
Gyeongsang National University Hospital
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Yongho Choe
Gyeongsang National University Hospital
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Heewon Lee
Ewha Womans University College of Pharmacy
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Min-Gyu Jeon
Gyeongsang National University College of Medicine
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Jin-Ho Park
Gyeongsang National University College of Medicine
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Hae Sook Noh
Gyeongsang National University College of Medicine
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Yun-Hong Cheon
Gyeongsang National University Hospital
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Hee Jin Park
Gyeongsang National University College of Medicine
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Kyunglim Park
Yonsei University College of Medicine
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Sung Jae Shin
Yonsei University College of Medicine
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Kyunglim Lee
Ewha Womans University College of Pharmacy
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Sang-Il Lee
Gyeongsang National University College of Medicine
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Abstract

Background and Purpose Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP remains undefined in rheumatoid arthritis (RA). In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. Experimental Approach 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 the sera of RA patients and compared to those with osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLS) 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-FLS and CIA mice. Key Results Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were higher in HRF/TCTP TG mice, and lower in KD mice, compared to that in wild-type littermates. HRF/TCTP levels were higher in the sera, synovial fluid, synovium, and FLS of patients with RA than control groups. Serum levels of HRF/TCTP correlated well with disease activity of 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 effects in a murine tuberculosis model. Conclusion and Implications Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.