Michal A Rahat
Carmel Medical Center and Technion, Israel
Title: The role of the pro-angiogenic protein EMMPRIN in the pathogenesis of psoriatic arthritis
Biography
Biography: Michal A Rahat
Abstract
Angiogenesis is an essential component in the pathophysiology of psoriatic arthritis (PsA). Extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is a multifunctional protein that enhances angiogenesis by inducing VEGF and MMPs. Using ELISA, we assessed the concentrations of angiogenic factors (EMMPRIN, VEGF, MMP-9, MMP-7, MMP-3, MMP-2, MMP-14) in serum of 56 PsA patients with active disease, 41 PsA patients in remission, 33 patients with active rheumatoid arthritis (RA) and 33 healthy controls. PsA patients demonstrated significantly elevated levels of serum EMMPRIN, MMP-7, MMP-14 compared to RA patients (p<0.001, p<0.01 p<0.01 respectively) and to controls (p<0.0001 p<0.01, p<0.01 respectively). The levels of VEGF (p<0.05), MMP-14 (p<0.05), MMP-2 (p<0.0001), TIMP-2 (p<0.001), OPG (p<0.001) and RANKL (p<0.001) were higher in PsA patients with active disease compared to patients in remission. Serum concentrations of MMP-9 were significantly lower in RA and PsA patients vs., controls (p<0.0001) with no significant difference between the two disease groups. To evaluate the mediating role of EMMPRIN in fibroblast macrophage interactions and angiogenesis, we co-cultured in vitro the human fibroblast HT1080 cell line with the human monocytic like U937 or Mono Mac 6 cell lines. Secretion of EMMPRIN, VEGF and MMP-9 were synergistically enhanced in the co-culture (p<0.01 for all three proteins relative to single cultures), and addition of the blocking anti-EMMPRIN antibody reduced VEGF (1.7-folds, p<0.001) and MMP-9 levels (1.4-folds, p<0.001) in the co-culture. Higher numbers of closed lumens were generated when the endothelial cell-line EaHy926 was incubated with supernatants derived from the co-cultures relative to each single culture (p<0.05) whereas, when EMMPRIN was blocked by the antibody, this number significantly decreased (p<0.05). EaHy926 cells incubated with the co-culture supernatants were more rapidly migrated to close a scratch, compared to cells where EMMPRIN was specifically blocked by antibody (p<0.05). Our results implicate EMMPRIN as an important mediator of angiogenesis promoting fibroblast monocytes interactions, suggesting it has a central role in the pathophysiology of PsA.