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

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.

• Authors: Young-Sool Hah, Young Jun Koh, Hye Song Lim, Hyun-Ok Kim, Yun-Hong Cheon, Hae Sook Noh, Kyu Yun Jang, Sang Yong Lee, Gyun Min Lee, Gou Young Koh, Sang-Il Lee
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 15 Issue 4 Pg. R85 (Aug 14 2013) ISSN: 1478-6362 [Electronic] England
• PMID: 23945080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietins
• Antirheumatic Agents
• Immunoglobulin G
• Receptors, Tumor Necrosis Factor
• Recombinant Proteins
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Etanercept

Topics

• Angiopoietins (antagonists & inhibitors)
• Animals
• Antirheumatic Agents (pharmacology)
• Arthritis, Experimental
• Arthritis, Rheumatoid (pathology)
• Enzyme-Linked Immunosorbent Assay
• Etanercept
• Immunoglobulin G (pharmacology)
• Immunohistochemistry
• Mice
• Mice, Inbred DBA
• Neovascularization, Pathologic (drug therapy, pathology)
• Receptors, Tumor Necrosis Factor
• Recombinant Proteins (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)