Jong-Sung Park1, Seol-Hee Kim2, Kwangmeyung Kim3, Cheng-Hao Jin4, Ki Young Choi5, Jiyeon Jang1, Yuri Choi1, A-Ryeong Gwon1, Sang-Ha Baik1, Ui Jeong Yun1, Su Young Chae1, Seulki Lee6, Young Mo Kang7, Kang Choon Lee1, Thiruma V Arumugam8, Mark P Mattson9, Jae Hyung Park10, Dong-Gyu Jo1. 1. School of Pharmacy, Sungkyunkwan University, Suwon, Korea. 2. School of Pharmacy, Sungkyunkwan University, Suwon, Korea Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea. 3. Biomedical Research Center, Korea Institute of Science and Technology, Seoul, Korea. 4. Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, China. 5. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA. 6. Russell 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. Department of Internal Medicine (Rheumatology), Kyungpook National University School of Medicine, Daegu, Korea. 8. School of Pharmacy, Sungkyunkwan University, Suwon, Korea Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, Singapore, Singapore. 9. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 10. Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.