Results The addition of TNF-alpha and M-CSF was sufficient to induce RA synovial macrophage-and monocyte-osteoclast differentiation in the absence of OPGL. This was evidenced by the formation of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor, cathepsin K-positive multinucleated cells on glass coverslips and lacunar resorption pits on dentine slices. When IL-1alpha was added to this cultures together with TNF-alpha, the number of lacunar resorption pits were increased. It was found that anti-TNF-alpha inhibited osteoclast formation by RA synovial macrophages and monocytes and that although the number of TRAP-positive multinucleated cells was not changed, inhibition of pit formation was seen when anti-IL-1alpha was added to RA macrophage and monocyte cultures. OPG, however, showed no effect on osteoclast formation and activation induced by TNF-alpha and IL-1alpha. Conclusion This study has shown that TNF-alpha induces RA synovial macrophage-and monocyte-osteoclast differentiation and that IL-1alpha activates osteoclasts to resorb bone. This osteoclast formation and activation is independent of OPGL signalling system. The new mechanism, inflammatory bone resorption, may represent an important role in the RA joint destruction and osteoporosis. REFERENCES1 Kobayashi K, Takahashi N, Jimi E, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction.
Japan Arthritis Res Ther 2003, 5(Suppl 3):1 (DOI 10.1186/ar800) Apoptosis is a principal mechanism in metazoans by which superfluous or potentially harmful cells are eliminated. Deregulation of this process leads to a variety of diseases such as cancer and autoimmune diseases. Stimuli that can induce apoptosis are relatively diverse, and include the death factors (Fas ligand, tumor necrosis factor and TRAIL), DNA damage, and oxidative stress. Regardless of the origin of the apoptotic stimulus, commitment to apoptosis leads to activation of caspases, a family of cysteine proteases. Cleavage of a select group of cellular substrates by caspases is responsible for the morphological and biochemical changes that characterize apoptotic cell death. The degradation of nuclear DNA into nucleosomal units is one of the features of apoptotic cell death, and is mediated by a caspase-activated DNase (CAD). Cells deficient in CAD undergo cell death without the DNA fragmentation, but CAD-null mice did not show any adverse phenotypes. A close examination of the apoptotic cells in these mice indicated that apoptotic cells are always in macrophages. It seems that at an early stage of apoptosis, the dying cells present an 'eat me signal' on their surface. This signal is recognized by macrophages for engulfment, and DNase II in the lysosomes of macrophages degrades DNA of apoptotic cells. Mice deficient in both CAD and DNase II genes were established, and the development of various organs was found to be severely impaired in these mutant mice. The mice accumulated a large amount of undigested DNA in macrophages in various tissues during development. This accumulation of DNA in macrophages activated the innate immunity to induce the expression of the interferon β gene. The interferon thus produced seems to be responsible for the impaired tissue development. These results indicate that the degradation of DNA during apoptotic cell death is an essential step of apoptosis to maintain mammalian homeostasis. Osteoarthritis (OA) has been considered a biomechanically driven, degenerative disease of cartilage. However, the OA disease process affects not only the cartilage, but also the entire joint structure; and within the bone, cartilage and synovium of affected joints, profound metabolic changes transpire, which include the production of growth factors, nitric oxide (NO), prostaglandins (PGs), leukotrienes (LTs), IL-1β, tumor necrosis factor alpha, IL-6, and IL-8. The autocrine production of IL-1β by OA cartilage has been of particular interest, since both ex vivo human and in vivo animal studies indicate that IL-1 antagonists effectively attenuate cartilage degradation. Microarray technology has demonstrated differential expression in OA cartilage of a variety of IL-1-induced, NFβB-dependent genes. Among IL-β-induced products of OA cartilage are various eicosanoids, which include E 2 , PGD 2 , LTB 4 , PGF 1α , PGF 2α and thromboxane. Treatment of OA cartilage with cyclooxygenase (COX) inhibitors increases LTB 4 production threefold to five...
IntroductionThe biological activity of interleukin (IL)-1 is tightly regulated by a specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1R2. The role of IL-1Ra has been well demonstrated in IL-1Ra deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown.MethodsWe generated IL-1R2 deficient mice in a C57BL/6 background and investigated the role of IL-1R2 in both lipopolysaccharide (LPS)-induced lethality by injecting 10 mg/kg E. coli LPS intraperitoneally (i.p.), and in systemic inflammatory responses induced by i.p. injections of 10 µg/kg IL-1β. Lethality was monitored daily and serum cytokine levels were measured at different time points by ELISA, respectively. Arthritis was induced by injecting i.p. 1.5 mg purified arthritogenic IgGs purified from K/BxN serum. Arthritis severity was assessed by clinical and histological scoring. Tissue mRNA levels of cytokines were measured by real-time PCR.ResultsIL-1R2 deficient mice bred normally and exhibited a grossly normal phenotype. IL-1R2 was selectively expressed by wild-type (WT), but not IL-1R2 deficient, neutrophils. The number of immune cells in bone marrow, spleen and peripheral blood was similar in IL-1R2 deficient and WT mice. The phagocytic function and oxidative burst of IL-1R2 deficient neutrophils were normal. The rate of LPS-induced mortality and the level of inflammatory responses to IL-1b were similar in IL-1R2 deficient mice and their WT littermates. In contrast, IL-1R2 deficiency was associated with aggravated arthritis severity. Levels of IL-6, IL-1β, CXCL-1 and CXCL-2 mRNA were significantly increased in ankles of IL-1R2 deficient mice. Immunohistochemical analyses indicated that IL-1R2 is mainly expressed by infiltrating neutrophils.ConclusionsThese data show that the decoy receptor IL-1R2 plays an important role during K/BxN serum transfer-induced inflammatory arthritis and suggest that neutrophils exert anti-inflammatory activities in arthritis by expressing IL-1R2. However, in contrast to IL-1Ra, IL-1R2 is not essential for normal homeostasis and systemic responses to LPS and acute IL-1 administration.
antibodies to parvovirus B19 results were further confirmed by Western blot. Results In 28 of 50 patients with RA (56%) and in 7/26 of the controls (26.9%) IgG antibodies to parvovirus B19 were detected (x2, p < 0.05). In 9 of 24 patients with OA and in 7/ 26 of controls IgG antibodies to parvovirus B19 were detected (x2, p > 0.05). In 11 of 50 patients with RA (22%) IgM antibodies to parvovirus B19 were detected and the results were further confirmed by Western blot, while in none of the patients with OA and in none of the controls were IgM antibodies observed (x2, p < 0.001 and p > 0.05, respectively). Conclusion The prevalence of antibodies to parvovirus B19 was found to be increased in patients with RA as compared to controls. In patients with OA the prevalence of antibodies to parvovirus B19 was found to be comparable to that in controls. These results indicate either that infection with parvovirus B19 may be implicated in the pathogenesis of RA, as previously discussed in the literature, or that some cases of chronic polyarthropathy due to parvovirus B19 may have been misdiagnosed as rheumatoid arthritis.
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