Open AccessSoluble VE‐cadherin in rheumatoid arthritis patients correlates with disease activity: Evidence for tumor necrosis factor α–induced VE‐cadherin cleavage
Author(s) -
Sidibé Adama,
Mannic Tiphaine,
Arboleas Mélanie,
Subileau Mariela,
GulinoDebrac Danielle,
Bouillet Laurence,
Jan Mary,
Vandhuick Thibault,
Le Loët Xavier,
Vittecoq Olivier,
Vilgrain Isabelle
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.33336
Subject(s) - medicine , rheumatoid arthritis , tumor necrosis factor alpha , immunology , tyrosine kinase , cancer research , endocrinology , receptor
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. Conclusion 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.