Bone Abstracts

Objectives: Synovial fluid glutamate concentrations increase in various arthritides. Activation of kainate (KA) and AMPA glutamate receptors (GluRs) increase interleukin 6 (IL6) release and cause arthritic pain respectively. GluR antagonists represent potential peripheral treatments for inflammatory arthritis and inflammatory mechanisms that contribute to osteoarthritis (OA). We hypothesised that AMPA and KA GluRs are expressed in arthritic joint tissues and that peripheral administration of NBQX (AMPA/KA GluR antagonist), would attenuate joint pathology in antigen-induced arthritis (AIA) in vivo.

Methods: Synovial inflammation and joint degradation were related to GluR immunohistochemistry in matched synovium and tibial plateaux from OA patients. NBQX was applied to three primary human osteoblast cell lines and mineralisation assessed. NBQX was injected intra-articularly into the affected knees of AIA rats at the time of arthritis induction. Knee swelling and gait patterns of AIA (n=15), AIA+NBQX (n=15), and naïve rats (n=6) were measured over 21 days. On day 21, joint tissues were taken for QRT-PCR, X-ray, magnetic resonance imaging (MRI), histology, and GluR immunohistochemistry.

Results: NBQX prevented mineralization in all cell lines. Human OA tissues showed extensive degradation and synovial inflammation with abundant GluR (AMPAR2, KA1) expression in areas of bone/cartilage remodeling. Similar GluR expression was observed in AIA rats, with less abundant GluR expression after NBQX treatment. NBQX treatment significantly reduced knee swelling (P<0.001, days 1–21), gait abnormalities (days 1–3), end-stage cartilage destruction (P<0.05), synovial inflammation (P<0.001), meniscal IL6 and whole joint cathepsin K mRNA expression (P<0.05). X-ray and MRI revealed a smoother articular surface; fewer bone erosions and less inflammation after NBQX treatment.

Discussion: AMPA/KA GluRs are abundantly expressed in human OA joints accompanied by synovial inflammation, and in a model of inflammatory arthritis. The attenuation of inflammation, pathology and pain in vivo, by intra-articular NBQX treatment, shows promise as a new disease-modifying drug for inflammatory- and osteo- arthritis.