Abstract
In previous studies we have found that FcγRI determines chondrocyte death and matrix metalloproteinase (MMP)-mediated cartilage destruction during IFN-γ-regulated immune complex arthritis (ICA). Binding of immune complexes (ICs) to FcγRI leads to the prominent production of oxygen radicals. In the present study we investigated the contribution of NADPH-oxidase-driven oxygen radicals to cartilage destruction by using p47phox-/- mice lacking a functional NADPH oxidase complex. Induction of a passive ICA in the knee joints of p47phox-/- mice resulted in a significant elevation of joint inflammation at day 3 when compared with wild-type (WT) controls as studied by histology. However, when IFN-γ was overexpressed by injection of adenoviral IFN-γ in the knee joint before ICA induction, a similar influx of inflammatory cells was found at days 3 and 7, comprising mainly macrophages in both mouse strains. Proteoglycan depletion from the cartilage layers of the knee joints in both groups was similar at days 3 and 7. Aggrecan breakdown in cartilage caused by MMPs was further studied by immunolocalisation of MMP-mediated neoepitopes (VDIPEN). VDIPEN expression in the cartilage layers of arthritic knee joints was markedly lower (between 30 and 60%) in IFN-γ-stimulated arthritic p47phox-/- mice at day 7 than in WT controls, despite significant upregulation of mRNA levels of various MMPs such as MMP-3, MMP-9, MMP-12 and MMP-13 in synovia and MMP-13 in cartilage layers as measured with quantitative RT-PCR. The latter observation suggests that oxygen radicals are involved in the activation of latent MMPs. Chondrocyte death, determined as the percentage of empty lacunae in articular cartilage, ranged between 20 and 60% at day 3 and between 30 and 80% at day 7 in WT mice, and was completely blocked in p47phox-/- mice at both time points. FcγRI mRNA expression was significantly lower, and FcγRII and FcγRIII were higher, in p47phox-/- mice than in controls. NADPH-oxidase-driven oxygen radical production determines chondrocyte death and aggravates MMP-mediated cartilage destruction during IFN-γ-stimulated IC-mediated arthritis. Upregulation of FcγRI by oxygen radicals may contribute to cartilage destruction.
Highlights
During rheumatoid arthritis (RA), large numbers of inflammatory cells, mainly macrophages, migrate into the synovial layer [1]
During immune complex arthritis (ICA), joint inflammation is downregulated by oxygen radicals, which is compensated for by IFN-γ To investigate the effect of the NADPH-oxidase-driven production of oxygen radicals on joint inflammation, ICA was induced in knee joints of p47phox-/- mice and their wild-type (WT) controls
We find that the amount of inflammatory mass was comparable in IFN-γ-stimulated knee joints of p47phox-/- mice and in their WT controls at both day 3 and day 7 after ICA induction (Fig. 2), suggesting that IFN-γ compensates for the aggravating effect of oxygen radicals on joint inflammation
Summary
During rheumatoid arthritis (RA), large numbers of inflammatory cells, mainly macrophages, migrate into the synovial layer [1]. Many of these macrophages become activated by mechanisms that are as yet unknown. Activated macrophages produce cytokines such as tumour necrosis factor-α (TNFα) and interleukin-1 (IL-1) and enzymes such as the metalloproteinase family, which can mediate severe cartilage destruction. A strong correlation was found between the number of activated macrophages and cartilage erosion [2]. Important triggers of macrophages are IgG-containing immune complexes, which are found in large amounts in the joints of many RA patients.
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