title: CD147 induces angiogenesis through a vascular endothelial growth factor and hypoxia-inducible transcription factor 1α-mediated pathway in rheumatoid arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is an inflammatory and angiogenic disease. However, the molecular mechanisms that promote angiogenesis in RA have not been clearly identified. Our objective was to study the role of CD147 in angiogenesis and determine whether the strategy in which CD147 is suppressed might be useful in reducing angiogenesis in RA.
  
  
  METHODS
  Correlations among expression levels of CD147, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1α (HIF-1α) were determined by immunohistochemistry staining. RA fibroblast-like synoviocytes (FLS) cells were cultured under various conditions, and the production of VEGF and HIF-1α was examined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The SCID mouse coimplantation model of RA (SCID-HuRAg) was established, mice were treated with CD147 monoclonal antibody, infliximab, or both CD147 and infliximab, and the volume of the grafts and the average vascular density were measured and analyzed. Western blot analyses were performed to examine the potential signaling pathways.
  
  
  RESULTS
  The expression levels of CD147 showed significantly positive correlations with VEGF and HIF-1α levels, as well as with vascular density, in RA synovium. After small interfering RNA transfection or after addition of specific antibodies for CD147, the production of VEGF and HIF-1α were significantly reduced. The expression of VEGF and HIF-1α decreased more after CD147 inhibition than after infliximab treatment in the engrafted tissues in SCID-HuRAg mice. The phosphatidylinositol 3-kinase/Akt pathway may be involved in this process.
  
  
  CONCLUSIONS
  CD147 induces up-regulation of VEGF and HIF-1α in RA FLS, further promotes angiogenesis, and leads to the persistence of synovitis. Inhibition of CD147 may be a promising target for novel therapeutic strategies.
authors.affiliation: First Affiliated Hospital and Fourth Military Medical University, Xi'an, China.
authors.forename: Cong-hua
authors.initials: CH
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.forename: Li-na
authors.initials: LN
authors.lastname: Chen
authors.forename: Jun-feng
authors.initials: JF
authors.lastname: Jia
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Jing-yao
authors.initials: JY
authors.lastname: Dai
authors.forename: Zhao-hui
authors.initials: ZH
authors.lastname: Zheng
authors.forename: Zhi-nan
authors.initials: ZN
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D051926:Basigin / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D051926:Basigin