IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

Toru Yago,Manabu Kawamoto,Shigeru Kotake,Naoyuki Kamatani,Takefumi Furuya,Yuki Nanke,Tsuyoshi Kobashigawa

doi:10.1186/ar2297

Abstract

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

Highlights

Rheumatoid arthritis is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone [1]
IL-23 directly induces osteoclastogenesis from human peripheral blood mononuclear cells (PBMC) To investigate whether rhIL-23 induces osteoclastogenesis, human PBMC were cultured with macrophage-colony stimulating factor (M-CSF) and rhIL-23 for 3 days; after non-adherent cells had been removed, adherent cells were cultured with M-CSF alone for 7 days
RhIL-23 did not induce osteoclastogenesis in a culture of human monocytes alone. These findings suggested that T cells were required for IL-23-induced human osteoclastogenesis from PBMC

Summary

Introduction

Rheumatoid arthritis is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone [1]. Our group and another have detected osteoclasts in synovial tissues [2] and eroded bone surfaces [3], suggesting that osteoclastic bone resorption is involved in the pathogenesis of rheumatoid arthritis (RA). It is well known that attenuating the activity of inflammatory cytokines in patients with RA inhibits bone resorption and destruction. IL-23 is composed of p19 and p40 subunits and shares a common p40 subunit with IL-12 [8]. IL-23 signals through the IL-23 receptor complex, which is composed of the IL-12 receptor β chain and the IL-23 receptor [9]. IL-23 was initially described as a cytokine able to induce the expression of IFN-γ in human CD45RO-positive (memory) T cells and to activate memory T cells to secrete

Methods

Results

Conclusion