Fc Gamma Receptors Enhance Development Of Bone Erosion In Experimental Arthritis Not By Increasing The Number Of Osteoclasts On The Bone Surface But By Stimulating Synovial Inflammation And Activation Of Osteoclasts

Background and objectives Rheumatoid arthritis is characterised by immune complex dependent chronic joint inflammation and severe cartilage and bone destruction. In earlier studies we showed that Fcg receptors (FcgRs) are crucial in regulating cartilage destruction during immune complex mediated antigen induced arthritis (AIA). Now we investigated the role of FcgRs in osteoclast-mediated bone erosion comparing development of AIA between mice lacking all FcgRs (FcgRI, II, III, IV -/- ) and their wild type controls. Material and methods AIA was induced by injection of 60 µg mBSA into the knee joint of FcγI, II, III, IV -/- and wild type (WT) control mice previously immunised with mBSA/CFA. Joint inflammation and bone destruction 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 precursors was defined through FACS analysis. Gene expression was measured using RT-PCR. Bone marrow derived cells osteoclastogenesis was quantified with TRAP staining. Results FcgRI, II, III, IV -/- mice showed a significant decrease in development of bone erosion in knee joints both at 7 and 21 days after induction of AIA (30% and 25% lower) when compared to WT controls. The immune response against mBSA (serum level of specific anti mBSA total IgG, IgG1, IgG2b and mBSA specific T-cell response) was comparable between the two strains. The percentage of osteoclast precursor population within the bone marrow (CD11b low-neg / Ly6C high , described to be upregulated during arthritis) was comparable between FcgRI, II, III, IV -/- and WT as was the ability of bone marrow cells to differentiate towards mature multinucleated osteoclasts upon stimulation with M-CSF and RANK-L. At day 7 after AIA induction, the decrease in bone erosion in FcgRI, II, III, IV -/- coincided with lowering of the number of inflammatory cells present within the joint (infiltrate and exudate 29% and 27% lower respectively compared to WT control). Interestingly no differences were found in the number of osteoclasts present at locations of bone erosion (measured by image analysis of TRAP staining) (32 +/ 13 osteoclasts/section in FcγRI/II/II/IV-/- versus 28 +/- 9 osteoclasts/section in WT) Furthermore gene expression of osteoclast activation factors (RANK-L, IL-1β, S100A8, Cathepsin K and TRAP) within the synovium were significantly lower in FcγRI/II/II/IV-/- (ddCt -2.7, -2.6, -3, -2.4, -3 respectively) suggesting that activation of osteoclasts may be driven by FcgRs. Conclusions FcgRs promote bone erosion in AIA not by increasing osteoclasts on the bone surface but by enhancing influx of inflammatory cells within the synovium and release of factors able to stimulate osteoclast activity.