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Open Access Research article

Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis

Young-Sool Hah1, Young Jun Koh2, Hye Song Lim3, Hyun-Ok Kim3, Yun-Hong Cheon3, Hae Sook Noh4, Kyu Yun Jang5, Sang Yong Lee6, Gyun Min Lee7, Gou Young Koh2* and Sang-Il Lee3*

Author Affiliations

1 Clinical Research Institute, Gyeongsang National University Hospital, 79 Gangnam-Ro, Jinju, 660-702, South Korea

2 National Research Laboratory of Vascular Biology and Stem Cells and Graduate School of Biomedical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 373-1 Guseong-dong, Daejeon, 305-701, South Korea

3 Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, 79 Gangnam-Ro, Jinju, 660-702, South Korea

4 Department of Biochemistry and Neurobiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, 79 Gangnam-Ro, Jinju, 660-702, South Korea

5 Department of Pathology, Medical School, Chonbuk National University, San 2-20, Geumam-dong, Jeonju, 561-756, South Korea

6 Department of Radiology, Medical School, Chonbuk National University, San 2-20, Geumam-dong, Jeonju, 561-756, South Korea

7 Department of Biological Sciences and Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), 373-1 Guseong-dong, Daejeon, 305-701, South Korea

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Arthritis Research & Therapy 2013, 15:R85  doi:10.1186/ar4265

Published: 14 August 2013

Abstract

Introduction

Angiogenesis plays a critical role in synovial inflammation and joint destruction in rheumatoid arthritis (RA). Vascular endothelial growth factor A (VEGF-A) and angiopoietins are two important mediators of synovial angiogenesis. We have previously developed a novel chimeric decoy receptor, namely, double-antiangiogenic protein (DAAP), which can both bind VEGF-A and angiopoietins and block their actions. This study was performed to evaluate the antiarthritic effect of DAAP and the combination effect with the tumor necrosis factor α (TNF-α) inhibitor in collagen-induced arthritis (CIA).

Methods

Recombinant DAAP, VEGF-Trap, Tie2-Fc and dimeric Fc proteins were produced and purified from CHO cells in large-scale bioreactors. CIA was induced in DBA/1 mice with type II collagen. The preventive effect of DAAP was determined and compared with other decoy receptors such as VEGF-Trap or Tie2-Fc, which block VEGF-A or angiopoietins, respectively. The clinical, radiographic, pathologic and immunohistochemical analyses were performed in CIA mice. The levels of matrix metalloprotease 3 (MMP-3) and interleukin 1β (IL-1β) were quantified by enzyme-linked immunosorbent assay, and receptor activator of nuclear factor κB ligand (RANKL) mRNA levels were measured by polymerase chain reaction. Finally, we investigated the combination effects of DAAP with a low dose of TNF-α decoy receptor (etanercept 10 mg/kg).

Results

On the basis of clinical and radiographic evaluation, DAAP had a much greater inhibitory effect than VEGF-Trap or Tie2-Fc on arthritis severity and bone destruction. These inhibitory effects were accompanied by significantly diminishing pathologic abnormalities, CD31-positive vasculature and synovial infiltration by F4/80-positive macrophages. The levels of MMP-3, IL-1β and RANKL were much lower in the DAAP-injected group than those of the control. Furthermore, DAAP showed a therapeutic effect and a combination effect with etanercept when injected after arthritis onset in established CIA.

Conclusions

DAAP has not only potent prophylactic effects on both inflammation and bone destruction but also therapeutic effects, alone and in combination with a TNF-α inhibitor in CIA mice. These results suggest that DAAP could be used as an effective new therapeutic agent for RA.