title: Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.
abstract: OBJECTIVE
  To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes.
  
  
  METHODS
  Immune complex-mediated arthritis (ICA) was passively induced by lysozyme-antilysozyme complexes in Fc gamma RI-, Fc gamma RIII-, and Fc gamma RII-knockout mice and their wild-type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]-mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid-related proteins 8 and 14 (MRP8 and MRP14, respectively).
  
  
  RESULTS
  Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in Fc gamma RIII-deficient mice and enhanced in mice lacking Fc gamma RII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP-mediated VDIPEN expression, was reduced in Fc gamma RIII(-/-) and Fc gamma RI(-/-) mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in Fc gamma RII(-/-) mice. In Fc gamma RI(-/-) and Fc gamma RIII(-/-) mice, VDIPEN expression was 90-99% lower, whereas in Fc gamma RII(-/-) mice, VDIPEN expression was increased 4-fold. Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in Fc gamma RII(-/-) arthritic joints.
  
  
  CONCLUSIONS
  During ICA, Fc gamma RIII is the dominant activating receptor mediating joint inflammation, whereas both Fc gamma RI and Fc gamma RIII are involved in cartilage destruction. Fc gamma RII inhibits both joint inflammation and severe cartilage destruction during ICA.
authors.affiliation: University Medical Centre St. Radboud, Nijmegen, The Netherlands.
authors.forename: K C A M
authors.initials: KC
authors.lastname: Nabbe
authors.forename: A B
authors.initials: AB
authors.lastname: Blom
authors.forename: A E M
authors.initials: AE
authors.lastname: Holthuysen
authors.forename: P
authors.initials: P
authors.lastname: Boross
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.forename: S
authors.initials: S
authors.lastname: Verbeek
authors.forename: P L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001168:Arthritis / Q000276:immunology* / Q000473:pathology*; D002356:Cartilage / Q000276:immunology / Q000473:pathology; D016923:Cell Death; D019902:Chondrocytes / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D016130:Immunophenotyping; D007719:Knee Joint / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D000936:Antigen-Antibody Complex; D017452:Receptors, IgG