title: AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis.
abstract: OBJECTIVE
  Synovial fluid glutamate concentrations increase in arthritis. Activation of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (GluRs) increase interleukin-6 (IL-6) release and cause arthritic pain, respectively. We hypothesised that AMPA and KA GluRs are expressed in human arthritis, and that intra-articular NBQX (AMPA/KA GluR antagonist) prevents pain and pathology in antigen-induced arthritis (AIA).
  
  
  METHODS
  GluR immunohistochemistry was related to synovial inflammation and degradation in osteoarthritis (OA) and rheumatoid arthritis (RA). A single intra-articular NBQX injection was given at induction, and knee swelling and gait of AIA and AIA+NBQX rats compared over 21 days, before imaging, RT-qPCR, histology and immunohistochemistry of joints. Effects of NBQX on human primary osteoblast (HOB) activity were determined.
  
  
  RESULTS
  AMPAR2 and KA1 immunolocalised to remodelling bone, cartilage and synovial cells in human OA and RA, and rat AIA. All arthritic tissues showed degradation and synovial inflammation. NBQX reduced GluR abundance, knee swelling (p<0.001, days 1-21), gait abnormalities (days 1-2), end-stage joint destruction (p<0.001), synovial inflammation (p<0.001), and messenger RNA expression of meniscal IL-6 (p<0.05) and whole joint cathepsin K (p<0.01). X-ray and MRI revealed fewer cartilage and bone erosions, and less inflammation after NBQX treatment. NBQX reduced HOB number and prevented mineralisation.
  
  
  CONCLUSIONS
  AMPA/KA GluRs are expressed in human OA and RA, and in AIA, where a single intra-articular injection of NBQX reduced swelling by 33%, and inflammation and degeneration scores by 34% and 27%, respectively, exceeding the efficacy of approved drugs in the same model. AMPA/KA GluR antagonists represent a potential treatment for arthritis.
authors.affiliation: Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Cleo S
authors.initials: CS
authors.lastname: Bonnet
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Gilbert
authors.affiliation: Arthritis Research UK Biomechanics and Bioengineering Centre, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Harvey
authors.affiliation: Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Bronwen A
authors.initials: BA
authors.lastname: Evans
authors.affiliation: Division of Pathophysiology and Repair, School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007719:Knee Joint / Q000000981:diagnostic imaging; D008297:Male; D008592:Menisci, Tibial / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism*; D010006:Osteoblasts; D010146:Pain / Q000276:immunology / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D015850:Interleukin-6; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
keywords: Inflammation; Knee Osteoarthritis; Rheumatoid Arthritis; Synovitis; Treatment