Premium
The role of glutamate signalling in rheumatoid arthritis
Author(s) -
Flood S.L.,
Duance V.C.,
Mason D.J.
Publication year - 2004
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.0959-9673.2004.0369x.x
Subject(s) - glutamate receptor , synovial joint , metabotropic glutamate receptor , chemistry , metabotropic glutamate receptor 2 , timp1 , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 5 , microbiology and biotechnology , biology , receptor , biochemistry , gene expression , medicine , pathology , osteoarthritis , alternative medicine , gene , articular cartilage
Rheumatoid arthritis (RA) is characterized by joint inflammation and destruction mediated by enhanced secretion of degradative enzymes and cytokines. Inflammation of the joint is accompanied by elevated levels of glutamate within the synovial fluid (McNearney et al . 2000). Glutamate has been shown to modulate bone cell phenotype (Chenu et al . 1998). We hypothesize that the elevated glutamate in synovial fluid that accompanies RA can induce phenotypic changes associated with synovial joint destruction. Methods The mRNA expression of glutamate receptors and transporters was investigated in tissues of the rat knee joint by RT‐PCR to determine which cell types are potentially responsive to glutamate. To determine whether extracellular glutamate affects synoviocyte phenotype, we have investigated the effect of different glutamate concentrations on human, primary, RA synoviocytes' enzyme and cytokine expression. Matrix metalloproteinases (MMPs) and tissue inhibibitors of MMPs (TIMPs) protein expression was determined by zymography, and IL‐6 release by RA synoviocytes was measured using an IL‐6 ELISA (R & D systems). Results RT‐PCR has revealed glutamate transporter (GLAST‐1) and ionotropic and metabotropic receptor mRNA expression in several tissues of the rat knee joint. Pro‐MMP2, TIMP1 and TIMP2 activity were all increased in the presence of high extracellular glutamate concentrations and in the presence of glutamate transporter inhibitors. The presence of glutamate transporter inhibitors also increased production of the cytokine IL‐6 but only at low glutamate concentrations. Discussion Our data show that many cells of the synovial joint have potential for responding to glutamate signals. Primary synoviocytes from RA patients increase MMP and TIMP expression in response to high extracellular glutamate and in the presence of glutamate transporter inhibitors which also increase IL‐6 production. We postulate therefore that the high levels of glutamate present in RA synovial fluid are having a pro‐inflammatory effect on synoviocytes. This may be mediated through the cytokine IL‐6, the synovial fluid levels of which correlate with RA disease activity. We have previously shown that IL‐6 treatment of RA synoviocytes induces the glutamate transporter (GLAST‐1) expression therefore indicating a feedback mechanism between IL‐6 and GLAST‐1 expression. We are currently investigating the effect of ionotropic glutamate receptor antagonists on the pheontype of RA synoviocytes to elucidate the specific signalling mechanisms involved.