Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Jong Sung Park, Seol Hee Kim, Kwang Meyung Kim, Cheng Hao Jin, Ki Young Choi, Jiyeon Jang, Yuri Choi, A. Ryeong Gwon, Sang Ha Baik, Ui Jeong Yun, Su Young Chae, Seulki Lee, Young Mo Kang, Kang Choon Lee, Thiruma V. Arumugam, Mark P. Mattson, Jae Hyung Park, Dong Gyu Jo

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41 Citations (Scopus)

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 antisensemediated 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-KB, 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.

Original languageEnglish
Pages (from-to)267-274
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Park, J. S., Kim, S. H., Kim, K. M., Jin, C. H., Choi, K. Y., Jang, J., Choi, Y., Gwon, A. R., Baik, S. H., Yun, U. J., Chae, S. Y., Lee, S., Kang, Y. M., Lee, K. C., Arumugam, T. V., Mattson, M. P., Park, J. H., & Jo, D. G. (2015). Inhibition of Notch signalling ameliorates experimental inflammatory arthritis. Annals of the Rheumatic Diseases, 74(1), 267-274. https://doi.org/10.1136/annrheumdis-2013-203467