title: Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor α-induced VE-cadherin cleavage.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor α (TNFα) is the major mediator of inflammation in RA, related to vascular injury by targeting VE-cadherin, an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE-cadherin processing by TNFα and their occurrence in RA.
  
  
  METHODS
  Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNFα to study VE-cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE-cadherin cytoplasmic domain and extracellular domain (VE-90) generation, respectively. VE-90 was analyzed at baseline and at the 1-year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months.
  
  
  RESULTS
  TNFα induced a time-dependent shedding of VE-90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE-cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNFα-induced VE-cadherin cleavage. Of major importance, VE-90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1-year followup.
  
  
  CONCLUSIONS
  These findings provide the first evidence of VE-cadherin proteolysis upon TNFα stimulation and suggest potential clinical relevance of soluble VE-cadherin in management of RA.
authors: INSERM Unité 1036, Joseph Fourier University-Grenoble 1, and CEA Grenoble, Grenoble, France.
authors: Adama
authors: A
authors: Sidibé
authors: Tiphaine
authors: T
authors: Mannic
authors: Mélanie
authors: M
authors: Arboleas
authors: Mariela
authors: M
authors: Subileau
authors: Danielle
authors: D
authors: Gulino-Debrac
authors: Laurence
authors: L
authors: Bouillet
authors: Mary
authors: M
authors: Jan
authors: Thibault
authors: T
authors: Vandhuick
authors: Xavier
authors: X
authors: Le Loët
authors: Olivier
authors: O
authors: Vittecoq
authors: Isabelle
authors: I
authors: Vilgrain
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011994:Recombinant Proteins; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D017077:Culture Media, Conditioned; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D000099152:Cadherin 5