Blockade of CTGF Restores Aberrant Ostoclastgenesis in Collagen Induced Arthritis (CIA) Mice Through Inhibition of Th-17 Differentiation

Kazuhisa Nozawa¹, Maki Fujishiro², Ayako Yamaguchi¹, Mikiko Kawasaki², Shouzou Ichinose², Mitsuaki Yanagida², Kazuhisa Iwabuchi², Keigo Ikeda³, Shinji Morimoto⁴, Megumi Morioka⁵, Yoshinari Takasaki⁶ and Iwao Sekigawa³, ¹Rheumatology, Juntendo University School of Medicine, Tokyo, Japan, ²Institute for Environment and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan, ³Internal Medicine 2, Juntendo University Urayasu Hospital, Tomioka, Urayasu, Chiba, Japan, ⁴Juntendo University Urayasu Hospital, Tokyo, Japan, ⁵Nihon Nosan Corporation, Nihon Nosan Corporation, Kanagawa, Japan, ⁶Internal Medicine and Rheumatology,, Juntendo University School of Medicine, Tokyo, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Animal models, inflammatory arthritis, interleukins (IL), osteoclastogenesis and rheumatoid arthritis

Session Information

Title: Rheumatoid Arthritis: Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Our previous study demonstrated changes in the profiles of serum protein biomarkers in infliximab-treated rheumatoid arthritis (RA) patients using a novel approach to proteomic research. Several proteins exhibited vast changes in expression after infliximab treatment, and we have reported connective tissue growth factor (CTGF) appeared to be a potent strong biomarker in infliximab-treated RA patients. Furthermore, we also found that CTGF was upregulated in both serum level and tissue expression of patients with RA, and that CTGF was related to disease progression of RA through abnormal activation of osteoclasts in vitro. To extend our research project, this study was conducted to clarify roles of CTGF for RA pathogenesis. To investigate more precise roles of CTGF for RA pathogenesis, we analyzed effects of blockade against CTGF pathway on the progression of arthritis in collagen induced arthritis (CIA) mouse.

Methods: CIA was introduced in DBA/1J mice by immunization in combination with typeIIcollagen and complete Freund’s adjuvant (CFA). The efficacy and mechanisms for prevention of the arthritis were evaluated in the mice treated with or without neutralizing anti-CTGF monoclonal antibody (mAb).

Results: The blockade of CTGF by anti-CTGF mAb treatment significantly ameliorated the arthritis compared to the non-treated controls. Moreover, serum levels of C reactive protein (CRP) and matrix metalloproteinase (MMP)-3 reduced in the CTGF-treated mice. The blockade of CTGF decreased interleukin (IL)-17 and IL-21 production from purified CD4+ T lymphocytes. Although gene expression of retinoic-acid-receptor-related orphan receptors gamma t (RORgt) was not suppressed by anti-CTGF mAb treatment, those of interferon regulatory factor-4 (IRF-4) and IkappaBzeta, which are other important molecules for Th-17 differentiation, were suppressed. In addition, the blockade of CTGF inhibited pathological T lymphocytes proliferation against typeIIcollagen restimulation extra vivo. Moreover, aberrant sRANKL/MCSF-induced osteoclastgenesis of CD14+ progenitor cells in CIA was restored by anti-CTGF mAb treatment.

Conclusion: The present study demonstrated that the blockade of CTGF significantly prevented a progression of arthritis in CIA mice. The administration of anti-CTGF mAb had suppressive effects on aberrant pathological T cells proliferation and Th17 differentiation in CIA mice. In addition, the blockade of CTGF pathway might restore aberrant ostoclastgenesis of CIA through direct effect to CD14+ osteoclastic progenitor cells and indirect effects for Th-17 differentiation. CTGF may become a new target molecule for treatment of RA.

Disclosure:

K. Nozawa,
None;

M. Fujishiro,
None;

A. Yamaguchi,
None;

M. Kawasaki,
None;

S. Ichinose,
None;

M. Yanagida,
None;

K. Iwabuchi,
None;

K. Ikeda,
None;

S. Morimoto,
None;

M. Morioka,
None;

Y. Takasaki,
None;

I. Sekigawa,
None.

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/blockade-of-ctgf-restores-aberrant-ostoclastgenesis-in-collagen-induced-arthritis-cia-mice-through-inhibition-of-th-17-differentiation/