title: Fcgamma receptors directly mediate cartilage, but not bone, destruction in murine antigen-induced arthritis: uncoupling of cartilage damage from bone erosion and joint inflammation.
abstract: OBJECTIVE
  To determine the relationship between synovial inflammation and the concomitant occurrence of cartilage and bone erosion during conditions of variable inflammation using various Fcgamma receptor knockout (FcgammaR(-/-)) mice.
  
  
  METHODS
  Antigen-induced arthritis (AIA) was introduced in the knee joints of various FcgammaR(-/-) mice and wild-type controls. Joint inflammation and cartilage and bone destruction levels were determined by histologic analysis. Cathepsin K, RANKL, and osteoprotegerin (OPG) levels were detected by immunolocalization.
  
  
  RESULTS
  In FcgammaRIIb(-/-) mice, which lack the inhibiting Fcgamma receptor IIb, levels of joint inflammation and cartilage and bone destruction were significantly higher (infiltrate 93%, exudate 200%, cartilage 100%, bone 156%). AIA in mice lacking activating FcgammaR types I, III, and IV, but not FcgammaRIIb (FcR gamma-chain(-/-) mice), prevented cartilage destruction completely. In contrast, levels of bone erosion and joint inflammation were comparable with their wild-type controls. Of great interest, in arthritic mice lacking activating FcgammaR types I, II, and III, but not IV (FcgammaRI/II/III(-/-) mice), levels of joint inflammation were highly elevated (infiltrate and exudate, 100% and 188%, respectively). Cartilage destruction levels were decreased by 92%, whereas bone erosion was increased by 200%. Cathepsin K, a crucial mediator of osteoclasts, showed a strong correlation with the amount of inflammation but not with the amount of activating FcgammaR, which was low in osteoclasts. RANKL, but not OPG, levels were higher in the inflammatory cells of arthritic knee joints of FcgammaRI/II/III(-/-) mice versus wild-type mice.
  
  
  CONCLUSIONS
  Activating FcgammaR are crucial in mediating cartilage destruction independently of joint inflammation. In contrast, FcgammaR are not directly involved in bone erosion. Indirectly, FcgammaR drive bone destruction by regulating joint inflammation.
authors.affiliation: Rheumatology Department, Radboud University Medical Centre, Nijmegen, The Netherlands. P.vanlent@reuma.umcn.nl
authors.forename: Peter L
authors.initials: PL
authors.lastname: van Lent
authors.forename: Lilyanne
authors.initials: L
authors.lastname: Grevers
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.forename: Teun J
authors.initials: TJ
authors.lastname: de Vries
authors.forename: Karin C
authors.initials: KC
authors.lastname: Nabbe
authors.forename: Sjef
authors.initials: S
authors.lastname: Verbeek
authors.forename: Birgit
authors.initials: B
authors.lastname: Oppers
authors.forename: Annet
authors.initials: A
authors.lastname: Sloetjes
authors.forename: Arjen B
authors.initials: AB
authors.lastname: Blom
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001169:Arthritis, Experimental / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology*; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation; D007124:Immunoenzyme Techniques; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D013585:Synovitis / Q000378:metabolism / Q000473:pathology
chemical_list: D000936:Antigen-Antibody Complex; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D017452:Receptors, IgG; D016173:Macrophage Colony-Stimulating Factor; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse