title: Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis.
abstract: OBJECTIVE
  To determine the role of CCL21 and its receptor CCR7 in the pathogenesis of rheumatoid arthritis (RA).
  
  
  METHODS
  Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays. Finally, the mechanism by which CCL21 mediates angiogenesis was determined by Western blot analysis and endothelial cell chemotaxis and tube formation assays.
  
  
  RESULTS
  CCL21, but not CCL19, at concentrations present in the RA joint, induced human microvascular endothelial cell (HMVEC) migration that was mediated through CCR7 ligation. Suppression of the phosphatidylinositol 3-kinase pathway markedly reduced CCL21-induced HMVEC chemotaxis and tube formation; however, suppression of the ERK and JNK pathways had no effect on these processes. Neutralization of either CCL21 in RA synovial fluid or CCR7 in HMVECs significantly reduced the induction of HMVEC migration and/or tube formation by RA synovial fluid. We further demonstrated that CCL21 is angiogenic, by showing its ability to promote blood vessel growth in Matrigel plugs in vivo at concentrations that are present in RA joints.
  
  
  CONCLUSIONS
  Angiogenesis is dependent on endothelial cell activation, migration, and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. This study identified a novel function of CCL21 as a mediator of RA angiogenesis, supporting CCL21/CCR7 as a therapeutic target in RA.
authors.affiliation: University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Pickens
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Chamberlain
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Talarico
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mandelin
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000494:pharmacology; D054421:Chemokine CCL21 / Q000494:pharmacology / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054400:Receptors, CCR7 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054400:Receptors, CCR7; D019869:Phosphatidylinositol 3-Kinases