Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis

Sachi Tsunemi,Tsuyoshi Iwasaki,Misato Takagi-Kimura,Hajime Sano,Kunio Matsumoto,Tomoko Tamaoki,Sachie Kitano,Shuji Kubo

doi:10.1186/ar4252

Abstract

IntroductionHepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice.MethodsArthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4+ T cells stimulated with allogeneic spleen cells.ResultsThe intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4+ T cells stimulated with allogeneic spleen cells.ConclusionsThese results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4+ T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA.

Highlights

Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization
We observed the expression of NK4 protein in HGF and c-Met expression in the synovia of SKG mice and rheumatoid arthritis (RA) patients To examine whether the HGF/c-Met pathway is involved in the pathogenesis of RA, we first determined the expression of HGF and c-Met in the synovia of SKG mice
HGF was expressed in the synovial lining and fibroblastic cells of RA and OA synovial tissues (Figure 2C)

Summary

Introduction

Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. RA is characterized by aggressive synovial expansion and invasion and subsequent destruction of the underlying cartilage and bone. There is mounting evidence that angiogenic inducers, such as vascular endothelial growth factor (VEGF), play a pivotal role in RA [4,5,6]. Hepatocyte growth factor (HGF) has angiogenic activity for vascular endothelial cells [8]. NK4 has been isolated as a competitive antagonist for HGF and the c-Met receptor [12], and subsequent studies have shown that NK4 inhibits the angiogenic response induced by basic fibroblast growth factor (bFGF) and VEGF [13]

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Conclusion