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A1.25 FC gamma receptors enhance bone erosion in experimental arthritis by stimulating synovial inflammation and activation of osteoclasts
  1. I Di Ceglie1,
  2. S Verbeek2,
  3. P van der Kraan1,
  4. W van den Berg1,
  5. P van Lent1
  1. 1Experimental Rheumatology, Radboud University, Nijmegen
  2. 2Human Genetics, Leiden University Medical Center, Leiden, Netherlands

Abstract

Background and objectives Rheumatoid Arthritis (RA) is characterised by bone destruction in joints caused by enhanced activity of osteoclasts. Ig-G containing immune complexes (ICs) correlate with disease severity and bone erosion and are recognised by Fc gamma receptors (FcgγRs) on myeloid cells.

Here we investigated the role of FcgγRs in osteoclast-mediated bone erosion in an immune complex mediated model of arthritis (AIA antigen induced arthritis) using mice lacking the complete set of FcgγRs.

Material and methods AIA was induced by injection of mBSA into the knee joint of FcγRI, II, III, IV-/- and WT control mice previously immunised with mBSA/CFA. Joint inflammation, bone destruction and number of TRAP positive osteoclasts was determined in total knee joints sections. mBSA antibody titers were measured using ELISA and T cells response monitored with a lymphocyte stimulation test. Osteoclast precursor subsets were defined through FACS analysis. Gene expression was measured using RT-PCR.

Results The amount of bone erosionin the knee joint of FcgγRI, II, III, IV-/- mice was decreased compared to WT controls both at 7 and 21 days after induction of AIA. The immune response against mBSA (serum level of specific anti mBSA IgG and mBSA specific T-cell response) was comparable between the two strains. At day 7 after AIA induction, the decrease in bone erosion in FcgγRI, II, III, IV-/- coincided with lowering of macrophages within the synovium. The percentage of osteoclast precursor within the bone marrow (CD11blow-neg/ Ly6Chigh) was comparable between FcgγRI, II, III, IV-/- and WT. Although less macrophages were detected within the synovium, no differences were found in the number of mature osteoclasts present at locations of bone erosion, suggesting that mainly the activity of osteoclasts was affected in the KO animals. Levels of macrophage derived factors like IL-1β and S100A8, known to strongly induce osteoclast activity, were reduced both at gene expression level and protein level in the synovium of FcgγRI, II, III, IV-/- mice.

Conclusions FcgγRs promote bone erosion in AIA by enhancing influx of macrophages within the synovium and release of factors such as IL-1β and S100A8 able to stimulate osteoclast activity.

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