title: Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis.
abstract: BACKGROUND
  Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice.
  
  
  METHODS
  Arthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells.
  
  
  RESULTS
  The intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells.
  
  
  CONCLUSIONS
  These results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4⁺ T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA.
authors.forename: Sachi
authors.initials: S
authors.lastname: Tsunemi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Sachie
authors.initials: S
authors.lastname: Kitano
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Misato
authors.initials: M
authors.lastname: Takagi-Kimura
authors.forename: Shuji
authors.initials: S
authors.lastname: Kubo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tamaoki
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010446:Peptide Fragments / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor