title: Inhibition of notch signalling ameliorates experimental inflammatory arthritis.
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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Biomedical Research Center, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, China.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Jin
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Jang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: A-Ryeong
authors.initials: AR
authors.lastname: Gwon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Ui Jeong
authors.initials: UJ
authors.lastname: Yun
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.affiliation: 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.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine (Rheumatology), Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: 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.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D016207:Cytokines / Q000187:drug effects / Q000276:immunology*; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology*
chemical_list: D016207:Cytokines; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases
keywords: Arthritis; Inflammation; Rheumatoid Arthritis