Background/Purpose:

Rheumatoid arthritis is characterized by immune complex dependent chronic joint inflammation and severe cartilage and bone destruction. In earlier studies we showed that Fcγ receptors (FcγRs) are crucial in regulating cartilage destruction during immune complex mediated antigen induced arthritis (AIA)(1,2). In this study we investigated the role of FcγRs in osteoclast-mediated bone erosion comparing  development of AIA between mice lacking all  FcγRs (FcγRI,II,III,IV ^-/-)  and their wild type controls.

Methods:

AIA was induced by injection of 60 µg mBSA into the knee joint of FcγRI,II,III,IV^-/-and wild type (WT) control mice previously immunized with mBSA/CFA.  Joint inflammation and bone destruction was determined in total knee joints sections. mBSA antibody titers were measured  using ELISA and T cell response monitored with a lymphocyte stimulation test. The percentage of osteoclast precursors in the bone marrow was defined through FACS analysis. Gene expression was measured using RT-PCR and protein levels measured with ELISA or Luminex. S100A8 positive cells in the synovium were detected with immunostaining.

Results:

In FcγRI,II,III,IV ^-/- mice the development of bone erosion in knee joints was significantly reduced both at days 7 and 21  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, IgG2a, 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 FcγRI,II,III,IV ^-/- and WT controls. Moreover FcγRI,II,III,IV ^-/-  bone marrow cells  showed the same ability to differentiate towards osteoclasts upon stimulation with M-CSF and RANK-L in vitro.

At day 7 after AIA induction, the decrease in bone erosion in FcγRI,II,III,IV ^-/-  was associated with  a significantly decrease in 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 present in the number of mature osteoclasts present at locations of bone erosion along patella, femur and tibia ( 32 +/- 13 osteoclasts/section in FcγRI,II,II,IV-/-  versus 28 +/- 9 osteoclasts/section in  WT).  Gene expression of osteoclast activation factors (RANK-L, IL-1β, S100A8) within the synovium were however significantly lower in FcγRI,II,III,IV-/- (ddCt -2.7, -2.6, -3, respectively).  IL-1β and S100A8 were decreased also at the protein level in the synovium wash out and the immunostaining showed a significantly lower amount of S100A8-producing cells in the synovium of FcγR I,II,III,IV -/- animals compared to the WT.

Conclusion:

FcγRs promote bone erosion in AIA not by increasing the number of osteoclasts present on the bone surface but by enhancing influx and activation of inflammatory cells within the synovium thereby  releasing factors able to stimulate osteoclast activity.

(1) van Lent PL et al., Am J Pathol., 2001

(2) van Lent PL et al., Arthritis Rheum., 2010

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ablation-of-fc-gamma-receptors-leads-to-a-decreased-bone-erosion-in-experimental-arthritis-not-by-altering-osteoclast-numbers-within-the-inflamed-joint-but-by-inhibiting-osteoclast-activation/