title: Targeting the P2X7 receptor in rheumatoid arthritis: biological rationale for P2X7 antagonism.
abstract: OBJECTIVE
  This paper aims to explore the functional significance of the P2X7 receptor in preclinical models of rheumatoid arthritis.
  
  
  METHODS
  Preclinical studies in vivo were performed using the rat streptococcal cell wall (SCW) arthritis model. Ex vivo cultures of lipopolysaccharide (LPS)/benzoylbenzoyl adenosine triphosphate (BzATP)-stimulated human monocytes were generated to test the activities of a novel, highly specific inhibitor of human P2X7, AZD9056, on interleukin (IL)-1 and IL-18 release.
  
  
  RESULTS
  P2X7 receptor expression was detected in inflamed synovial tissue after onset of SCW-induced arthritis in rats. Inhibition of P2X7 therein led to reduced articular inflammation and erosive progression. No effect was noted on acute-phase responses. Ex vivo, AZD9056 inhibited IL-1 and IL-18 release to BzATP in LPS-primed human monocytes.
  
  
  CONCLUSIONS
  P2X7 receptor inhibition could represent a novel approach to the treatment of inflammatory arthritis. However, confirmatory clinical studies are warranted to further explore this possibility.
authors.affiliation: Glasgow Biomedical Research Centre, University of Glasgow, UK. iain.mcinnes@glasgow.ac.uk.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Simon
authors.initials: S
authors.lastname: Cruwys
authors.forename: Keith
authors.initials: K
authors.lastname: Bowers
authors.forename: Martin
authors.initials: M
authors.lastname: Braddock
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; C000589760:IL18 protein, human; D018836:Inflammation Mediators; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate