title: Pathogenic role of CXCR7 in rheumatoid arthritis.
abstract: OBJECTIVE
  The interaction between CXCL12 and its receptor, CXCR4, in the synovium of patients with rheumatoid arthritis (RA) is important for local inflammatory cell recruitment, angiogenesis, and cytokine production. CXCR7 was recently identified as an alternative receptor for CXCL12. We undertook this study to analyze the expression of CXCR7 in RA synovium and the pathogenic role of the CXCL12/CXCR7 pathway in RA.
  
  
  METHODS
  CXCR7 expression in RA synovial tissue was analyzed using immunohistochemistry, while expression of CXCR4 and CXCR7 on human umbilical vein endothelial cells (HUVECs) was examined using quantitative reverse transcription-polymerase chain reaction, and CXCR7 expression was also analyzed by flow cytometry. Tube formation and rat aortic ring angiogenesis assays were used to assess the effects of CCX733 (a CXCR7 antagonist) and AMD3100 (a CXCR4 antagonist) on CXCL12-induced angiogenesis. The effect of anti-CXCR4 monoclonal antibody (mAb) was also analyzed using a tube formation assay. The effects of CCX733 in a murine model of collagen-induced arthritis (CIA) were also evaluated.
  
  
  RESULTS
  CXCR7 was expressed on endothelial cells in RA synovium and also on unstimulated HUVECs. The expression of CXCR7 on HUVECs was markedly up-regulated by interleukin-1β (IL-1β) stimulation, and this overexpression was further enhanced by CXCL12 treatment. Incubation with CXCL12 also promoted angiogenic activity, with addition of IL-1β again augmenting the effect. CXCL12-induced angiogenesis was inhibited by both CXCR4 and CXCR7 antagonists and by anti-CXCR4 mAb. Furthermore, treatment with CCX733 significantly reduced the clinical arthritis scores and the numbers of vessels in the inflamed synovial tissue in mice with CIA.
  
  
  CONCLUSIONS
  CXCR7 and CXCR4 are both important for angiogenesis in RA synovium, making CXCR7 another potential target molecule for novel RA angiogenesis-blocking therapies.
authors.affiliation: Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Watanabe
authors.forename: Mark E T
authors.initials: ME
authors.lastname: Penfold
authors.forename: Akio
authors.initials: A
authors.lastname: Matsuda
authors.forename: Naho
authors.initials: N
authors.lastname: Ohyanagi
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kaneko
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D051381:Rats; D054387:Receptors, CXCR / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*; D014471:Umbilical Veins / Q000276:immunology / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; D054387:Receptors, CXCR; D019718:Receptors, CXCR4