NADPH-oxidase-driven oxygen radical production determines chondrocyte death and partly regulates metalloproteinase-mediated cartilage matrix degradation during interferon-γ-stimulated immune complex arthritis
© van Lent et al.; licensee BioMed Central Ltd. 2005
Received: 21 July 2004
Accepted: 19 April 2005
Published: 20 May 2005
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.
During rheumatoid arthritis (RA), large numbers of inflammatory cells, mainly macrophages, migrate into the synovial layer . 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 . Important triggers of macrophages are IgG-containing immune complexes, which are found in large amounts in the joints of many RA patients . In previous studies we have found, by comparing various experimental arthritis models, that severe cartilage destruction developed mainly when immune complexes were present . Severe cartilage destruction is thereby defined as chondrocyte death and cartilage matrix destruction. The latter is induced predominantly by metalloproteinases (MMPs), which are released in a latent form. Upon activation these enzymes degrade the collagen type II network in the cartilage resulting in irreversible erosion . During immune complex (IC)-mediated arthritides, synovial macrophages seemed to be dominant factors in the induction of severe cartilage destruction .
IgG-containing ICs communicate with macrophages with FcγR. Three classes have been described, and previous studies in our laboratory showed that absence of the activating FcγRI and FcγRIII completely abrogated severe cartilage destruction [7–9].
The mechanism of FcγR-mediated chondrocyte death and MMP-mediated cartilage destruction is not known. However, we found recently that FcγRI is the dominant activating FcγR causing cartilage destruction [10, 11]. In T cell-driven immune complex arthritis (ICA), chondrocyte death in FcγRI-/- was completely abrogated, whereas MMP-mediated cartilage destruction was significantly diminished . Moreover, ICA stimulated by local overexpression of the T cell factor IFN-γ showed pronounced chondrocyte death that was also completely mediated by FcγRI .
Binding of ICs to FcγRI causes intracellular signalling and triggers activation of the multicomponent enzyme NADPH oxidase, which catalyses the production of oxygen species . The latter have been shown to be involved in cell death [15, 16] and in the activation of metalloproteinases . The active central role in NADPH oxidase is as the transmembrane cytochrome b556, which comprises two subunits, gp91phox and p22phox. p47phox is the cytosolic component of the NADPH oxidase complex that translocates to the membrane and associates with cytochrome b556 to form the active complex that catalyses the reduction of oxygen to superoxide. Functionally, p47phox increases the binding of p67phox to cytochrome b556 about 100-fold [18–20]. IFN-γ strongly stimulates p91 and also the expression of FcγRI. Binding of ICs to FcγRI further increases NADPH oxidase activity . Phospholipase D-1 has been shown to be an important mediator between FcγRI signalling and the activation of NADPH oxidase [14, 22]. The combination of IFN-γ and FcγRI stimulation might therefore result in a strong stimulation of NADPH oxidase, catalysing the production of large amounts of superoxide.
In the present study we investigated the effect of NADPH-oxidase-driven oxygen radicals in the generation of severe cartilage destruction during IFN-γ-accelerated ICA. For that purpose mice in which the p47phox gene had been knocked out were used; they are unable to form a functional NADPH oxidase complex  and are therefore unable to make oxygen species by the NADPH oxidase pathway. However, other oxygen-radical-producing pathways remain intact. We found that chondrocyte death was completely abrogated, whereas MMP-mediated cartilage destruction was significantly inhibited. FcγRI expression was significantly downregulated; in contrast, MMP gene expression in the synovium was higher, suggesting that oxygen radicals are involved in the activation step of MMPs.
Materials and methods
NADPH-oxidase-deficient (C57BL/6-p47phox- /-) mice were generated as described previously , and lack the cytosolic p47phox subunit of the NADPH oxidase multicomponent system. The knockout mice were backcrossed to the C57BL6 background for 15 generations; C57BL/6 mice (obtained from the Jackson Laboratory, Bar Harbor, ME, USA) were used as controls. In some experiments p47phox- /- mice of intercross progeny (C57BL/6 × 129Sv) were used with their proper controls. Colonies were maintained at the National Institutes of Health (Bethesda, MD, USA). All mice were housed under specified pathogen-free conditions during breeding and experiments. Mice received autoclaved chow and acidified water ad libitum. Only healthy mice were used in the experiments and were age-matched (10 to 20 weeks) and sex-matched for each set of experiments. All experiments were approved by local authorities of the Animal Care and Use Committee (DEC 98.22) and performed by personnel certified by the Dutch Ministry of Well-being, Public Health and Culture.
Overexpression of IFN-γ in vivowith an adenoviral construct
The recombinant adenovirus encoding murine IFN-γ (AdIFN-γ) was generated as described previously . Knee joints of naive mice were injected intra-articularly with 6 μl of AdIFN-γ (107 plaque-forming units). At different time points (days 3 and 7), patellae with adjacent synovium were dissected in a standardised manner  and synovium biopsies were taken using a biopsy punch with a diameter of 3 mm. Total RNA was extracted in 1 ml of TRIzol reagent and used for quantitative PCR as described below. AdIFN-γ was injected intra-articularly 1 day before arthritis induction.
Induction of immune complex arthritis
ICA was passively induced by injecting 3 μg of poly-(L-lysine)-coupled lysozyme into the knee joints of mice that had previously (16 hours earlier) received, intravenously, polyclonal antibodies directed against lysozyme. These antibodies were raised in rabbits.
Histology of arthritic knee joints
Total knee joints of mice were isolated 3 and 7 days after arthritis onset. Mice were killed by cervical dislocation, knee joints were decalcified, dehydrated, and embedded in paraffin. Tissue sections (7 μm) were stained with haematoxylin and eosin. Seven sections spaced 70 μm apart representing the whole knee joint were measured to obtain a statistically justified result. Histopathological changes were scored by grading the inflammation on a scale from 0 (no inflammation) to 3 (severe inflamed joint) as the influx of inflammatory cells into synovium and joint cavity. To study proteoglycan (PG) depletion from cartilage matrix, sections were stained with safranin O followed by counterstaining with fast green. PG depletion (loss of red staining) from various cartilage layers was determined by using an arbitrary scale from 0 to 3. Normal cartilage was assigned the value 0, and cartilage fully depleted of PGs was taken as 3. Chondrocyte death was determined in total knee joint sections stained with haematoxylin and eosin. Chondrocyte death was determined as the percentage of the area of the cartilage containing empty lacunae in relation to the total area. All experiments were scored separately and independently from each other.
Immunohistochemical detection of the identification marker of macrophages
F4/80, a murine macrophage membrane antigen, was detected with a specific rat anti-mouse F4/80 IgG. Primary antibodies were detected with rabbit anti-rat IgG and avidin–horseradish peroxidase conjugate. Finally, sections were counterstained with Mayer's haematoxylin (Merck, Darmstadt, Germany).
Immunolocalisation of MMP-induced neoepitope (VDIPEN)
For immunohistochemical analysis of MMP-induced neoepitopes, sections were deparaffinised, rehydrated and digested with chondroitinase ABC (Sigma; 0.25 U/ml in 0.1 M Tris-HCl, pH 8.0) for 1 hour at 37°C, to remove chondroitin sulphate from the PGs. Sections were then treated for 20 min with 1% hydrogen peroxide in methanol and subsequently for 5 min with 0.1% (v/v) Triton X-100 in phosphate-buffered saline. After incubation for 20 min with 1.5% (v/v) normal goat serum, sections were incubated with affinity-purified anti-VDIPEN IgG overnight at 4°C. These antibodies were kindly provided by Irwin Singer and Ellen Bayne (Merck Research Laboratories, Rahway, NJ, USA) and have been extensively characterised previously [26, 27]. In addition, sections were incubated with biotinylated goat anti-rabbit IgG and binding was detected by avidin-peroxidase staining (Elite kit; Vector Labs, Inc., Burlingame, CA, USA). Development of the peroxidase product was performed by nickel enhancement, and counterstaining was performed with Orange G (2%) for 5 min.
Quantitative RT-PCR of synovium and cartilage
Synovial biopsies were taken from tissue adjacent to the suprapatellar ligament with a biopsy punch (diameter 3 mm). The cartilage layers from patellae and tibiae were isolated after decalcification with 5% EDTA for 4 hours at 4°C. Subsequently, patellae and tibiae were washed in 0.9% NaCl and the cartilage layer was carefully removed from the underlying bone with forceps and a dissection microscope. RNA was isolated with 1 ml of TRIzol reagent (Life Technologies, Breda, The Netherlands). Specific mRNA levels for various MMPs (MMP-2, MMP-3, MMP-9, MMP-12 and MMP-13), their inhibitors (TIMP-1, TIMP-2, TIMP-3 and TIMP-4) and FcγR (FcγRI, FcγRII and FcγRIII) were quantified with the ABI/PRISM 7000 Sequence Detection System (ABI/PE, Foster City, CA, USA). In brief, 1 μg of synovial RNA was used for RT-PCR. mRNA was reverse-transcribed to cDNA with the use of oligo(dT) primers; 1/20 of the cDNA was used in one PCR amplification. PCR was performed in SYBR Green Master Mix by using the following amplification protocol: 2 min at 50°C followed by 40 cycles of 15 s at 95°C and 1 min at 60°C, with data collection in the last 30 s. Message for murine glyceraldehyde-3-phosphate dehydrogenase, MMPs, MMP inhibitors and FcγR was amplified with specific primers (Biolegio, Malden, The Netherlands) for these molecules at a final concentration of 300 nM. Relative quantification of the PCR signals was performed by comparing the cycle threshold value (Ct) of the various molecules in the different samples after correction of the glyceraldehyde-3-phosphate dehydrogenase content for each individual sample to rule out confounding by variation of the RNA purification and reverse transcriptase steps.
During ICA, joint inflammation is downregulated by oxygen radicals, which is compensated for by IFN-γ
Oxygen radicals are not involved in mediating early PG depletion
Oxygen radicals aggravate MMP-mediated cartilage destruction during IFN-γ-accelerated ICA
In WT controls, the amount of VDIPEN staining varied from 5% in the patella to 55% in the lateral femur 3 days after arthritis induction. In p47phox-/- mice, VDIPEN staining in various cartilage layers was comparable to WT controls at that time point (Fig. 5a). At day 7 after arthritis induction, VDIPEN staining varied between 10 and 80% in WT controls. Interestingly, in knee joints of arthritic p47phox-/- mice, VDIPEN staining was significantly lower in the lateral femur, medial femur and lateral tibia (50%, 60% and 50% reduction, respectively) (Fig. 5b, and compare Fig. 5c with Fig. 5d) and values were not different from those found at day 3. These results indicate that oxygen radicals aggravate MMP-mediated cartilage damage during IC-mediated arthritis.
Oxygen radicals downregulate MMP mRNA levels within cartilage layers and inflamed synovium during ICA
Oxygen radicals upregulate FcγRI and downregulate FcγRII and FcγRIII during IFN-γ-stimulated ICA
Oxygen radicals determine chondrocyte death during IFN-γ-driven IC-mediated arthritis
In the present study we found that in the absence of NADPH-oxidase-generated oxygen radicals, IC-mediated joint inflammation was significantly enhanced in p47phox-/- mice. This might be due to a disruption in IC clearance because the removal of ICs from the joint determines the severity of arthritis . This is in line with a previous study in which it was shown that oxygen radicals are crucial in the clearance of foreign particles such as cell walls of microorganisms . Previously we found that injecting zymosan directly into the knee joint of p47phox-/- mice caused a strongly elevated joint inflammation due to retarded clearance and resulted in prominent granuloma formation within the synovia of these mice . In the present study we found that IFN-γ overexpression in the knee joint of p47phox-/- mice before ICA induction prevented the increase in joint inflammation, and no granuloma formation was found. IFN-γ is a potent upregulator of receptors involved in phagocytosis, such as FcγR and complement receptors, and might lead to an efficient removal of the small amount of ICs responsible for continuing arthritis within the knee joints of p47phox-/- mice. Macrophages form the dominant cell type within this model and these cells express large quantities of FcγR, largely responsible for IC clearance but also for the activation of the lining cells, driving arthritis . Interestingly, synovial expression of the inhibitory FcγRII, which has been shown to be the dominant FcγR involved in IC clearance , was upregulated in the synovium of IFN-γ-stimulated p47phox-/- mice, and because FcγRII does not need oxygen radicals for efficient clearance this might lead to a more efficient IC clearance.
Although the amount of infiltrated macrophages was not different between arthritic p47phox-/- mice and their WT controls, destruction of the cartilage matrix by MMPs was lower in the absence of oxygen radicals. Cytokines such as IL-1 and TNFα activate chondrocyte and synoviocytes to produce MMPs, which are released in an inactive form. These latent enzymes need an activation step to become able to degrade the cartilage matrix. MMP-3 is the crucial MMP involved in the activation of MMP-13, which forms the rate-limiting enzyme in the degradation of the collagen type II matrix, leading to erosion of the cartilage matrix . IFN-γ overexpression strongly increased MMP expression both in cartilage layers and in the synovium. This might be regulated directly by IFN-γ or indirectly in the synovium by the upregulation of FcγR and their subsequent activation by ICs. In the present study we found that inflamed synovia of IFN-γ-stimulated p47phox-/- mice showed a strong upregulation of various MMPs such as MMP-9, MMP-12 and MMP-13, whereas only a minor upregulation of MMP-3 and MMP-12 was found within the cartilage. In the synovium, only TIMP-1 and TIMP-2 were marginally upregulated, whereas in the cartilage no differences in TIMP expression were found. Because MMP-mediated cartilage destruction was lower in arthritic p47phox-/- mice, whereas MMP expression in the synovium and cartilage layers seemed higher, this might indicate that oxygen radicals, apart from inhibiting the gene expression of MMPs, are involved in their activation. Oxygen radicals have previously been shown to activate latent MMPs such as MMP-2 . In the present study we also found that oxygen radicals upregulate FcγRI. Binding of ICs to FcγRI leads to more oxygen radical production  and might form an amplification step in the activation of pro-MMPs.
An interesting difference in the contribution of oxygen radicals to MMP-mediated cartilage damage in p47phox-/- mice was found between arthritis induced by zymosan (ZIA) and that by ICs. During IFN-γ-stimulated ICA, oxygen radicals enhance MMP-cartilage damage, whereas during ZIA they inhibit it. An explanation for this discrepancy might be the cell type involved in mediating cartilage destruction. During ZIA, many polymorphonuclear cells (PMNs) infiltrate into the joint. Crucial enzymes released by PMNs are elastase and cathepsin G, which because of their highly positive charge are highly capable of penetrating cartilage and are then able to stimulate pro-MMPs into their active form, to generate VDIPEN neoepitopes . Under normal circumstances elastase activity is inhibited by synovial fluid inhibitors such as α2-macroglobulin, and no VDIPEN staining can be detected within the cartilage layers . However, in the absence of oxygen radicals the number of infiltrated PMNs was strongly increased during ZIA  and the amount of elastase might then overrule the inhibiting capacity of the synovial fluid.
Another parameter of severe cartilage destruction is chondrocyte death, which was completely abrogated in the absence of NADPH-oxidase-driven oxygen radicals. Chondrocyte death might be mediated by oxygen radicals released by the chondrocyte itself or by the inflamed synovium. Chondrocytes do express NADPH oxidase  and cytokines such as IL-1 are potent inducers of oxygen radicals in chondrocytes . The production of intracellular hydrogen peroxide inside the chondrocyte can cause disruption of the mitochondrial membrane, leading to apoptosis . However, earlier studies in our laboratory showed that FcγR activated synovium is of crucial importance in mediating chondrocyte death . During IFN-γ-accelerated ICA, the infiltrated macrophages become activated by ICs, mainly via FcγR. In the mouse knee joint, FcγRI is expressed not by chondrocytes but exclusively by macrophages (and not neutrophils) and becomes strongly upregulated by IFN-γ. Binding of ICs to FcγRI in particular and, to a lesser extent, to FcγRIII leads to the activation of oxygen radical production (Fig. 10). Apart from FcγRI stimulation, IFN-γ itself has been shown to upregulate the p91 and p47 components of the NADPH oxidase and might contribute to the enhanced superoxide generation .
p47phox-/- mice might also produce oxygen radicals by pathways other than the NADPH oxidase pathway . However, IFN-γ alone had no effect on chondrocyte death. Moreover, it has been shown that IFN-γ does not upregulate alternative ways of oxygen radical production in p47phox-/- mice . This indicates that chondrocyte death is completely mediated via NADPH oxidase. IFN-γ induces the upregulation of NADPH oxidase components and FcγRI . Stimulation of FcγRI by ICs might also lead to an enormous increase in oxygen radical production, mediating cartilage destruction (Fig. 10). Hydrogen peroxide might again be the most plausible oxygen species mediating chondrocyte death. Hydrogen peroxide can easily penetrate through cell membranes. Previous studies have shown that hydrogen peroxide, when injected into mouse knee joints, was able to induce considerable chondrocyte death, which might be induced by apoptosis . Hydrogen peroxide activates the opening of the mitochondrial permeability transition pore and the release of cytochrome c . In the cytoplasm, cytochrome c, in combination with Apaf-1, activates caspase-9, leading to the activation of caspase-3 and subsequent apoptosis .
NADPH oxidase and p47phox phosphorylation is strongly increased in leucocytes derived from synovial fluid of RA patients . Cytokines such as IFN-γ are potent candidates for the upregulation of NADPH oxidase . Moreover, ICs are found in considerable amounts in joints of many RA patients. These ICs might be responsible for a large part of NADPH oxidase activation via FcγRI stimulation, resulting in large quantities of oxygen radicals. The latter might mediate part of the severe cartilage destruction. Because FcγRI-mediated oxygen radical production might have a major function in mediating cartilage destruction during arthritis, this receptor might form a crucial target in combating this crippling disease.
FcγR are central to the regulation of severe cartilage destruction during arthritis mediated by ICs. These ICs bind to FcγR, and the stimulation of activating FcγR, especially on synovial macrophages, leads to the production of as yet unknown products responsible for cartilage destruction. Th1 cytokines such as IFN-γ strongly upregulate FcγR – mainly FcγRI – and its stimulation leads to an enhanced production of oxygen radicals via NADPH oxidase. Using p47-/- mice, which fail to produce oxygen radicals via NADPH oxidase, we have shown that during IFN-γ-stimulated IC-mediated arthritis, oxygen radicals completely determine chondrocyte death and aggravate MMP-mediated cartilage destruction. Blockade of signalling pathways regulating oxygen radical production via FcγR or by neutralising oxygen radicals directly may form new therapeutic methods of preventing severe cartilage destruction.
immune complex arthritis
reverse transcriptase polymerase chain reaction
tissue inhibitor of metalloproteinase
- Yanni G, Whelan A, Feighery C, Bresnihan B: Synovial tissue macrophages and joint erosion in rheumatoid arthritis. Ann Rheum Dis. 1994, 53: 39-44.PubMed CentralView ArticlePubMedGoogle Scholar
- Mulherin D, Fitzgerald O, Bresnihan B: Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 1996, 39: 115-124.View ArticlePubMedGoogle Scholar
- Cooke TD, Richer S, Hurd E, Jasin HE: Localization of antigen-antibody complexes in intra-articular collagenous tissues. Ann NY Acad Sci. 1975, 256: 10-24.View ArticlePubMedGoogle Scholar
- van Meurs JB, van Lent PL, Holthuysen AE, Singer II, Bayne EK, van den Berg WB: Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. Arthritis Rheum. 1999, 42: 1128-1139. 10.1002/1529-0131(199906)42:6<1128::AID-ANR9>3.0.CO;2-2.View ArticlePubMedGoogle Scholar
- van Meurs J, van Lent P, Stoop R, Holthuysen A, Singer I, Bayne E, Mudgett JS, Poole R, Billinghurst C, van der Kraan P, et al: Cleavage of aggrecan at the Asn341-Phe342 site coincides with the initiation of collagen damage in murine antigen-induced arthritis: a pivotal role for stromelysin 1 in matrix metalloproteinase activity. Arthritis Rheum. 1999, 42: 2074-2084. 10.1002/1529-0131(199910)42:10<2074::AID-ANR7>3.0.CO;2-5.View ArticlePubMedGoogle Scholar
- Van Lent PL, Holthuysen AE, Van Den Bersselaar LA, Van Rooijen N, Joosten LA, Van De Loo FA, Van De Putte LB, Van Den Berg WB: Phagocytic lining cells determine local expression of inflammation in type II collagen-induced arthritis. Arthritis Rheum. 1996, 39: 1545-1555.View ArticlePubMedGoogle Scholar
- Ravetch JV: Fc receptors: rubor redux. Cell. 1994, 78: 553-560. 10.1016/0092-8674(94)90521-5.View ArticlePubMedGoogle Scholar
- Ravetch JV, Bolland S: IgG Fc receptors. Annu Rev Immunol. 2001, 19: 275-290. 10.1146/annurev.immunol.19.1.275.View ArticlePubMedGoogle Scholar
- Verbeek JS, Hazenbos WL, Capel PJ, Van De Winkel JG: The role of FcR in immunity: lessons from gene targeting in mice. Res Immunol. 1997, 148: 466-474. 10.1016/S0923-2494(97)82673-9.View ArticlePubMedGoogle Scholar
- Fossati-Jimack L, Ioan-Fascinay A, Reininger L, Chicheportiche Y, Watanabe N, Saito T, Hofhuis FM, Gessner JE, Schiller C, Schmidt RE, et al: Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an anti erythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcγ receptor III. J Exp Med. 2000, 191: 1293-1302. 10.1084/jem.191.8.1293.PubMed CentralView ArticlePubMedGoogle Scholar
- Van Lent PL, Nabbe K, Blom AB, Holthuysen AE, Sloetjes A, Van De Putte LB, Verbeek S, Van Den Berg WB: Role of activatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and cartilage destruction during experimental antigen-induced arthritis. Am J Pathol. 2001, 159: 2309-2320.PubMed CentralView ArticlePubMedGoogle Scholar
- Nabbe KC, Blom AB, Holthuysen AE, Boross P, Roth J, Verbeek S, Van Lent PL, Van Den Berg WB: Coordinate expression of activating Fcγ receptors I and III and inhibiting Fcγ receptor II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis. Arthritis Rheum. 2003, 48: 255-265. 10.1002/art.10721.View ArticlePubMedGoogle Scholar
- Nabbe KC, van Lent PL, Holthuysen AE, Kolls JK, Verbeek S, van den Berg WB: FcγRI up-regulation induced by local adenoviral-mediated interferon-γ production aggravates chondrocyte death during immune complex-mediated arthritis. Am J Pathol. 2003, 163: 743-752.PubMed CentralView ArticlePubMedGoogle Scholar
- Melendez AJ, Bruetschy L, Floto RA, Harnett MM, Allen JM: Functional coupling of FcγRI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1. Blood. 2001, 98: 3421-3428. 10.1182/blood.V98.12.3421.View ArticlePubMedGoogle Scholar
- Valencia A, Moran J: Reactive oxygen species induce different cell death mechanisms in cultured neurons. Free Radic Biol Med. 2004, 36: 1112-1124. 10.1016/j.freeradbiomed.2004.02.013.View ArticlePubMedGoogle Scholar
- Nair VD, Yuen T, Olanow CW, Sealfon SC: Early single bifurcation of pro- and anti-apoptotic states during oxidative stress. J Biol Chem. 2004, 279: 27494-27501. 10.1074/jbc.M312135200.View ArticlePubMedGoogle Scholar
- Yoon SO, Park SJ, Yoon SY, Yun CH, Chung AS: Sustained production of H2O2 activates pro-matrix metalloproteinase-2 through receptor tyrosine inases/phosphatidylinositol 3-kinase/NF-κB pathway. J Biol Chem. 2002, 277: 30271-30282. 10.1074/jbc.M202647200.View ArticlePubMedGoogle Scholar
- Deleo FR, Allen LA, Apicella M, Nauseef WM: NADPH oxidase activation and assembly during phagocytosis. J Immunol. 1999, 163: 6732-6740.PubMedGoogle Scholar
- Park HS, Kim IS, Park JW: Phosphorylation induces conformational changes in the leukocyte NADPH oxidase subunit p47phox. Biochem Biophys Res Commun. 1999, 259: 38-42. 10.1006/bbrc.1999.0721.View ArticlePubMedGoogle Scholar
- Vignais PV: The superoxide-generating NADPH oxidase:structural aspects and activation mechanism. Cell Mol Life Sci. 2002, 59: 1428-1459. 10.1007/s00018-002-8520-9.View ArticlePubMedGoogle Scholar
- Woolhiser MR, Okayama Y, Gilfillan AM, Metcalfe DD: IgG-dependent activation of human mast cells following up-regulation of FcγRI by IFN-γ. Eur J Immunol. 2001, 31: 3298-3307. 10.1002/1521-4141(200111)31:11<3298::AID-IMMU3298>3.0.CO;2-U.View ArticlePubMedGoogle Scholar
- Melendez AJ, Harnett MM, Allen JM: Crosstalk between ARF6 and protein kinase Calpha in FcγRI-mediated activation of phospholipase D1. Curr Biol. 2001, 5 (11): 869-874. 10.1016/S0960-9822(01)00260-3.View ArticleGoogle Scholar
- Jackson SH, Gallin JI, Holland SM: The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med. 1995, 182: 751-758. 10.1084/jem.182.3.751.View ArticlePubMedGoogle Scholar
- Lei D, Lancaster JR, Joshi MS, Nelson S, Stoltz D, Bagby GJ, Odom G, Shellito JE, Kolls JK: Activation of alveolar macrophages and lung host defenses using transfer of the interferon-gamma gene. Am J Physiol. 1997, 272: L852-L859.PubMedGoogle Scholar
- Van Meurs JB, Van Lent PL, Joosten LA, Van der Kraan PM, Van den Berg WB: Quantification of mRNA levels in joint capsule and articular cartilage of the murine knee joint by RT-PCR: kinetics of stromelysin and IL-1 mRNA levels during arthritis. Rheumatol Int. 1997, 16: 197-205. 10.1007/BF01330296.View ArticlePubMedGoogle Scholar
- Singer II, Kawka DW, Bayne EK, Donatelli SA, Weidner JR, Williams HR, Ayala JM, Mumford RA, Lark MW, Glant TT: VDIPEN, a metalloproteinase-generated neoepitope, is induced and immunolocalized in articular cartilage during inflammatory arthritis. J Clin Invest. 1995, 95: 2178-2186.PubMed CentralView ArticlePubMedGoogle Scholar
- Singer II, Scott S, Kawka DW, Bayne EK, Weidner JR, Williams HR, Mumford RA, Lark MW, McDonell J, Christen AJ, et al: Aggrecanase and metalloproteinase-specific aggrecan neo-epitopes are induced in the articular cartilage of mice with collagen II-induced arthritis. Osteoarth Cartil. 1997, 5: 407-418.View ArticleGoogle Scholar
- Wipke BT, Wang Z, Nagengast W, Reichert DE, Allen PM: Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes. J Immunol. 2004, 172: 7694-7702.View ArticlePubMedGoogle Scholar
- Mardiney M, Jackson SH, Spratt SK, Li F, Holland SM, Malech HL: Enhanced host defense after gene transfer in the murine p47phox-deficient model of chronic granulomatous disease. Blood. 1997, 89: 2268-2275.PubMedGoogle Scholar
- Van de Loo FA, Bennink MB, Arntz OJ, Smeets RL, Lubberts E, Joosten LA, van Lent PL, Coenen-de Roo CJ, Cuzzocrea S, Segal BH, et al: Deficiency of NADPH oxidase components p47phox and gp91phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models. Am J Pathol. 2003, 163: 1525-1537.PubMed CentralView ArticlePubMedGoogle Scholar
- Van Lent PL, Holthuysen AE, Van Rooijen N, van de Putte LB, van den Berg WB: Local removal of phagocytic synovial lining cells by clodronate-liposomes decreases cartilage destruction during collagen type II arthritis. Ann Rheum Dis. 1998, 57: 408-413.PubMed CentralView ArticlePubMedGoogle Scholar
- van Lent PL, Nabbe KC, Boross P, Blom AB, Roth J, Holthuysen A, Sloetjes A, Verbeek S, van den Berg W: The inhibitory receptor FcγRII reduces joint inflammation and destruction in experimental immune complex-mediated arthritides not only by inhibition of FcγRI/III but also by efficient clearance and endocytosis of immune complexes. Am J Pathol. 2003, 163: 1839-1848.PubMed CentralView ArticlePubMedGoogle Scholar
- van Meurs J, van Lent P, Holthuysen A, Lambrou D, Bayne E, Singer I, van den Berg W: Active matrix metalloproteinases are present in cartilage during immune complex-mediated arthritis: a pivotal role for stromelysin-1 in cartilage destruction. J Immunol. 1999, 163: 5633-5639.PubMedGoogle Scholar
- Biemond P, Swaak AJ, Koster JF: Protective factors against oxygen free radicals and hydrogen peroxide in rheumatoid arthritis synovial fluid. Arthritis Rheum. 1984, 27: 760-765.View ArticlePubMedGoogle Scholar
- Van Lent PL, van den Berg WB, Schalkwijk J, van de Putte LB, van den Bersselaar L: The impact of protein size and charge on its retention in arthritic cartilage. J Rheumatol. 1987, 14: 798-805.PubMedGoogle Scholar
- Moulton PJ, Goldring MB, Hancock JT: NADPH oxidase of chondrocytes contains an isoform of the gp91phox subunit. Biochem J. 1998, 329: 449-451.PubMed CentralView ArticlePubMedGoogle Scholar
- Lo YY, Conquer JA, Grinstein S, Cruz TF: Interleukin-1 beta induction of c-fos and collagenase expression in articular chondrocytes: involvement of reactive oxygen species. J Cell Biochem. 1998, 69: 19-29. 10.1002/(SICI)1097-4644(19980401)69:1<19::AID-JCB3>3.0.CO;2-Y.View ArticlePubMedGoogle Scholar
- Tada-Oikawa S, Hiraku Y, Kawanishi M, Kawanishi S: Mechanism for generation of hydrogen peroxide and change of mitochondrial membrane potential during rotenone-induced apoptosis. Life Sci. 2003, 73: 3277-3288. 10.1016/j.lfs.2003.06.013.View ArticlePubMedGoogle Scholar
- van Lent PL, van Vuuren AJ, Blom AB, Holthuysen AE, van de Putte LB, van de Winkel JG, van den Berg WB: Role of Fc receptor gamma chain in inflammation and cartilage damage during experimental antigen-induced arthritis. Arthritis Rheum. 2000, 43: 740-752. 10.1002/1529-0131(200004)43:4<740::AID-ANR4>3.0.CO;2-0.View ArticlePubMedGoogle Scholar
- Yang S, Madyastha P, Ries W, Key LL: Characterization of interferon gamma receptors on osteoclasts: effect of interferon gamma on osteoclastic superoxide generation. J Cell Biochem. 2002, 84: 645-654. 10.1002/jcb.10074.View ArticlePubMedGoogle Scholar
- Gupta JW, Kubin M, Hartman L, Cassatella M, Trinchieri G: Induction of expression of genes encoding components of the respiratory burst oxidase during differentiation of human myeloid cell lines induced by tumor necrosis factor and gamma-interferon. Cancer Res. 1992, 52: 2530-2537.PubMedGoogle Scholar
- Schalkwijk J, van den Berg WB, van de Putte LB, Joosten LA: Hydrogen peroxide suppresses the proteoglycan synthesis of intact articular cartilage. J Rheumatol. 1985, 12: 205-210.PubMedGoogle Scholar
- Yang JC, Cortopassi GA: Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome c. Free Radic Biol Med. 1998, 24: 624-631. 10.1016/S0891-5849(97)00367-5.View ArticlePubMedGoogle Scholar
- Budihardjo I, Oliver H, Lutter M, Luo X, Wang X: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 1999, 15: 269-290. 10.1146/annurev.cellbio.15.1.269.View ArticlePubMedGoogle Scholar
- El Benna J, Hayem G, Dang PM, Fay M, Chollet-Martin S, Elbim C, Meyer O, Gougerot-Pocidalo MA: NADPH oxidase priming and p47phox phosphorylation in neutrophils from synovial fluid of patients with rheumatoid arthritis and spondylarthropathy. Inflammation. 2002, 26: 273-278. 10.1023/A:1021460517468.View ArticlePubMedGoogle Scholar
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