PMID- 23945080
OWN - NLM
STAT- MEDLINE
DCOM- 20150910
LR  - 20211021
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 15
IP  - 4
DP  - 2013 Aug 14
TI  - Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A 
      and angiopoietins attenuates collagen-induced arthritis.
PG  - R85
LID - 10.1186/ar4265 [doi]
AB  - 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 alpha (TNF-alpha) 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 1beta (IL-1beta) were quantified by 
      enzyme-linked immunosorbent assay, and receptor activator of nuclear factor kappaB 
      ligand (RANKL) mRNA levels were measured by polymerase chain reaction. Finally, 
      we investigated the combination effects of DAAP with a low dose of TNF-alpha 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-1beta 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-alpha inhibitor in CIA mice. 
      These results suggest that DAAP could be used as an effective new therapeutic 
      agent for RA.
FAU - Hah, Young-Sool
AU  - Hah YS
FAU - Koh, Young Jun
AU  - Koh YJ
FAU - Lim, Hye Song
AU  - Lim HS
FAU - Kim, Hyun-Ok
AU  - Kim HO
FAU - Cheon, Yun-Hong
AU  - Cheon YH
FAU - Noh, Hae Sook
AU  - Noh HS
FAU - Jang, Kyu Yun
AU  - Jang KY
FAU - Lee, Sang Yong
AU  - Lee SY
FAU - Lee, Gyun Min
AU  - Lee GM
FAU - Koh, Gou Young
AU  - Koh GY
FAU - Lee, Sang-Il
AU  - Lee SI
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130814
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Angiopoietins)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (vascular endothelial growth factor A, mouse)
RN  - OP401G7OJC (Etanercept)
SB  - IM
MH  - Angiopoietins/*antagonists & inhibitors
MH  - Animals
MH  - Antirheumatic Agents/*pharmacology
MH  - Arthritis, Experimental
MH  - Arthritis, Rheumatoid/*pathology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Etanercept
MH  - Immunoglobulin G/pharmacology
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Inbred DBA
MH  - Neovascularization, Pathologic/drug therapy/pathology
MH  - Receptors, Tumor Necrosis Factor
MH  - Recombinant Proteins/pharmacology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors
PMC - PMC3978684
EDAT- 2013/08/16 06:00
MHDA- 2015/09/12 06:00
PMCR- 2013/08/14
CRDT- 2013/08/16 06:00
PHST- 2012/09/07 00:00 [received]
PHST- 2013/08/14 00:00 [accepted]
PHST- 2013/08/16 06:00 [entrez]
PHST- 2013/08/16 06:00 [pubmed]
PHST- 2015/09/12 06:00 [medline]
PHST- 2013/08/14 00:00 [pmc-release]
AID - ar4265 [pii]
AID - 10.1186/ar4265 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2013 Aug 14;15(4):R85. doi: 10.1186/ar4265.