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Inhibition of Notch signalling ameliorates experimental inflammatory arthritis
  1. Jong-Sung Park1,
  2. Seol-Hee Kim1,2,
  3. Kwangmeyung Kim3,
  4. Cheng-Hao Jin4,
  5. Ki Young Choi5,
  6. Jiyeon Jang1,
  7. Yuri Choi1,
  8. A-Ryeong Gwon1,
  9. Sang-Ha Baik1,
  10. Ui Jeong Yun1,
  11. Su Young Chae1,
  12. Seulki Lee6,
  13. Young Mo Kang7,
  14. Kang Choon Lee1,
  15. Thiruma V Arumugam1,8,
  16. Mark P Mattson9,10,
  17. Jae Hyung Park2,
  18. Dong-Gyu Jo1
  1. 1School of Pharmacy, Sungkyunkwan University, Suwon, Korea
  2. 2Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea
  3. 3Biomedical Research Center, Korea Institute of Science and Technology, Seoul, Korea
  4. 4Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, China
  5. 5Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
  6. 6Russell H. Morgan Department of Radiology and Radiological Science, Center for Cancer Nanotechnology Excellence, Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA
  7. 7Department of Internal Medicine (Rheumatology), Kyungpook National University School of Medicine, Daegu, Korea
  8. 8Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, Singapore, Singapore
  9. 9Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA
  10. 10Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Professor Dong-Gyu Jo, School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-Dong, Suwon 440-746, Korea; jodg@skku.edu, or Professor Jae Hyung Park, Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, 300 Cheoncheon-Dong, Suwon 440-746, Korea; jhpark1@skku.edu

Abstract

Objective To test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.

Methods Collagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.

Results The data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.

Conclusions These results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

  • Arthritis
  • Inflammation
  • Rheumatoid Arthritis

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