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

Research output: Contribution to journalArticle

33 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

Fingerprint

Experimental Arthritis
Rheumatoid Arthritis
Amyloid Precursor Protein Secretases
Cytokines
Arthritis
Pharmacology
Immunization
Matrix Metalloproteinase 3
Collagen Type II
Neutrophil Infiltration
Enzyme Inhibitors
Intercellular Adhesion Molecule-1
Fibroblasts
Inbred C57BL Mouse
Infiltration
Transgenic Mice
Chickens
Assays
Animals
Up-Regulation

ASJC Scopus subject areas

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

Cite this

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

In: Annals of the Rheumatic Diseases, Vol. 74, No. 1, 01.01.2015, p. 267-274.

Research output: Contribution to journalArticle

Park, JS, Kim, SH, Kim, KM, Jin, CH, Choi, KY, Jang, J, Choi, Y, Gwon, AR, Baik, SH, Yun, UJ, Chae, SY, Lee, S, Kang, YM, Lee, KC, Arumugam, TV, Mattson, MP, Park, JH & Jo, DG 2015, 'Inhibition of Notch signalling ameliorates experimental inflammatory arthritis', Annals of the Rheumatic Diseases, vol. 74, no. 1, pp. 267-274. https://doi.org/10.1136/annrheumdis-2013-203467
Park, Jong Sung ; Kim, Seol Hee ; Kim, Kwang Meyung ; Jin, Cheng Hao ; Choi, Ki Young ; Jang, Jiyeon ; Choi, Yuri ; Gwon, A. Ryeong ; Baik, Sang Ha ; Yun, Ui Jeong ; Chae, Su Young ; Lee, Seulki ; Kang, Young Mo ; Lee, Kang Choon ; Arumugam, Thiruma V. ; Mattson, Mark P. ; Park, Jae Hyung ; Jo, Dong Gyu. / Inhibition of Notch signalling ameliorates experimental inflammatory arthritis. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 1. pp. 267-274.
@article{907dc82609a14ea4935f739a227620bb,
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 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.",
author = "Park, {Jong Sung} and Kim, {Seol Hee} and Kim, {Kwang Meyung} and Jin, {Cheng Hao} and Choi, {Ki Young} and Jiyeon Jang and Yuri Choi and Gwon, {A. Ryeong} and Baik, {Sang Ha} and Yun, {Ui Jeong} and Chae, {Su Young} and Seulki Lee and Kang, {Young Mo} and Lee, {Kang Choon} and Arumugam, {Thiruma V.} and Mattson, {Mark P.} and Park, {Jae Hyung} and Jo, {Dong Gyu}",
year = "2015",
month = "1",
day = "1",
doi = "10.1136/annrheumdis-2013-203467",
language = "English",
volume = "74",
pages = "267--274",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "1",

}

TY - JOUR

T1 - Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

AU - Park, Jong Sung

AU - Kim, Seol Hee

AU - Kim, Kwang Meyung

AU - Jin, Cheng Hao

AU - Choi, Ki Young

AU - Jang, Jiyeon

AU - Choi, Yuri

AU - Gwon, A. Ryeong

AU - Baik, Sang Ha

AU - Yun, Ui Jeong

AU - Chae, Su Young

AU - Lee, Seulki

AU - Kang, Young Mo

AU - Lee, Kang Choon

AU - Arumugam, Thiruma V.

AU - Mattson, Mark P.

AU - Park, Jae Hyung

AU - Jo, Dong Gyu

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84918502975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84918502975&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2013-203467

DO - 10.1136/annrheumdis-2013-203467

M3 - Article

C2 - 24255545

AN - SCOPUS:84918502975

VL - 74

SP - 267

EP - 274

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 1

ER -