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

Abstract

IntroductionAngiogenesis 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).MethodsRecombinant 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).ResultsOn 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.ConclusionsDAAP 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.

The pathogenic role of angiogenesis in rheumatoid arthritis

“…Hence, Trebananib is currently being tested in clinical trials for the cancer treatment [179]. Double anti-angiogenic protein (DAAP), a dimeric decoy receptor with strong binding affinity to Ang1, Ang2 and VEGF [180], could markedly reduce CIA joint vascularization. However, the effect of Trebananib and DAAP on RA patients remains undetermined.…”

Relationship between VEGF Gene Polymorphisms and Serum VEGF Protein Levels in Patients with Rheumatoid Arthritis

“…Neovascularization, or angiogenesis, is a complex process leading to formation of new blood vessels from the pre-existing vascular network of the tissue. Synovial angiogenesis may plays a critical role in the early stage of RA by promoting inflammatory cell infiltration and the development of pannus, aggressive tumor like fibrovascular granulation tissue, which eventually leads to joint destruction [ 4 – 7 ]. However, the molecular mechanisms, which participate in the promotion of the angiogenesis in rheumatoid arthritis, have not been identified [ 8 ].…”

Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway

“…Therefore, the function of VEGF is concentrated and has stronger specificity (27). VEGF may additionally increase permeability of blood capillaries and is the blood vessel anti-reflection molecule that exhibits the strongest biological effect, >5 million times more potent compared with histamine substances (28). The results of the present study suggested that gambogic acid significantly suppressed the activation of VEGF protein expression, blocking activation of the VEGF signaling pathway in RA rats.…”

“…It is an endothelial cell mitogen and promotes fission of endothelial cells in order to promote neovascularization. The VEGF receptor is located in vascular endothelial cells (28). Therefore, the function of VEGF is concentrated and has stronger specificity (27).…”