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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preventing joint destruction is one of the most challenging issues in treating patients with rheumatoid arthritis (RA), and I propose that intracellular signaling pathways in osteoclasts and synovial fibroblastic cells (SFCs) can be good therapeutic targets. Osteoclasts are primarily involved in the bone destruction in RA joints, and SFCs support osteoclast differentiation and activation by producing various proinflammatory cytokines including receptor activator of NF-kappaB ligand (RANKL), the osteoclast differentiation factor belonging to the tumor necrosis factor-alpha superfamily. Suppressing c-Src pathways by adenovirus vector-mediated C-terminal Src family kinase (Csk) gene or Ras/extracellular-regulating kinase (ERK) pathways by introducing dominant negative Ras (Ras(DN)) adenovirus reduced osteoclastic bone resorption as well as the abnormal proliferation and interleukin-6 production of SFCs, and the local injection of these viruses ameliorated the joint destruction in adjuvant arthritis rats. Moreover, chondrogenic differentiation of SFCs could be induced by stimulating activin receptor-like kinase 3 pathways.
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PMID:Intracellular signal transduction pathways: good therapeutic targets for joint destruction in rheumatoid arthritis. 1702 17

Research into the bone destruction associated with rheumatoid arthritis has highlighted the importance of the interplay of the immune and skeletal systems. Arthritic bone destruction is attributable to the defective control of osteoclastogenesis by T cells. We revealed that excessive expression of receptor activator of NF-kappaB ligand (RANKL) and a paucity of interferon-gamma underlie the enhanced osteoclastogenesis in arthritis. The interdisciplinary research field called osteoimmunology has attracted further attention after identification of a number of unexpected bone phenotypes in mice lacking immunomodulatory molecules. Accumulating evidence suggests that the immune and skeletal systems share not only cytokines but also various signaling molecules, transcription factors, and membrane receptors. Thus, bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent. This emerging field will be of great importance for a better understanding and treatment of rheumatic diseases.
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PMID:Osteoimmunological insight into bone damage in rheumatoid arthritis. 1702 70

Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-kappaB ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-kappaB. Both receptors activate the PI3K and MAPK pathways, which promote cell proliferation and survival. SHIP1 is essential for normal bone homeostasis, as mice lacking the protein exhibit osteoporosis resulting from increased numbers of hyper-resorptive osteoclasts. In this study, we show that BMMs from SHIP1 null mice respond to M-CSF, but not receptor activator of NF-kappaB ligand, by increasing Akt activation. In consequence, there are up-regulation of D-type cyclins, down-regulation of the cyclin-dependent kinase inhibitor p27, and, therefore, increased phosphorylation of the retinoblastoma protein and cell proliferation. Surprisingly, cell survival of wild-type and knockout BMMs is unaltered. Finally, osteoclastogenesis and periarticular bone erosions are markedly increased in SHIP1(-/-) mice with inflammatory arthritis, a condition characterized by increased M-CSF expression. The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine.
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PMID:SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. 1714 80

Dendritic cells (DC) are the mononuclear cells that initiate adaptive immune responses. Osteoclasts (OC) are the multinucleated giant cells that resorb bone. As previously described for human conventional DC (cDC), we demonstrate that murine cDC, either in vitro generated from Fms-like tyrosine kinase 3 (Flt3)+ bone marrow progenitors or ex vivo purified from spleen, are able to develop into OC in response to M-CSF and receptor activator of NF-kappaB ligand (RANKL) in vitro. This transdifferentiation is driven by the immune environment that controls cDC maturation, cell fusion, tartrate-resistant acid phosphatase (TRAP) and bone resorption activities. Only immature cDC have the capacity to become OC since mature cDC or plasmacytoid DC do not. Additions of the pro-inflammatory cytokines, such as IL-1beta and TNF-alpha, or human rheumatoid synovial fluid, increase murine cDC transdifferentiation into OC, whereas IFN-alpha inhibits it. The adaptive cytokine, IFN-gamma, inhibits cDC fusion while IL-4 increases it. IL-2, IFN-gamma and IL-4 inhibit TRAP and bone resorption activities contrary to IL-10, which enhances both activities. A putative new "immune multinucleated giant cell" unable to resorb bone, which is formed owing to IL-4, is underlined. The future analysis of cDC transdifferentiation into OC in murine models of inflammatory arthritis will give us the quantitative importance of this phenomenon in vivo.
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PMID:Murine dendritic cell transdifferentiation into osteoclasts is differentially regulated by innate and adaptive cytokines. 1730 26

In autoimmune arthritis, activation of T cells induces bone destruction through receptor activator of NF-kappaB ligand (RANKL) . Recent study revealed interleukin-17 (IL-17) -producing helper T cell subset (Th17) , but not IFN-gamma-producing Th1, to be responsible for bone destruction. Here we summarize the current understanding of osteoclast differentiation and activation in the context of osteoimmunology.
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PMID:[Osteoclast differentiation and activation]. 1740 76

Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis. Because activation of osteoclasts is central to the pathogenesis of bone erosion in patients with rheumatoid arthritis (RA), we investigated the influence of AjA on osteoclast differentiation and survival. Osteoclast cultures were established by stimulation of RAW264.7 cells and primary mouse bone marrow cultures with receptor activator of NF-kappaB ligand (RANKL). Simultaneous addition of AjA (15 and 30 microM) and RANKL to both culture systems significantly suppressed development of multinucleated osteoclasts (osteoclastogenesis) in a dose dependent manner, as determined by quantification of multinuclear, tartrate-resistant acid phosphatase (TRAP)-positive cells. AjA impaired growth of RAW264.7 monocytes and prevented further osteoclast formation in cultures in which osteoclastogenesis had already begun. Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature.
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PMID:Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells. 1778 50

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.
Arthritis Res Ther 2007
PMID:IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. 1788 76

Inhibition of NF-kappaB is known to be effective in reducing both inflammation and bone destruction in animal models of arthritis. Our previous study demonstrated that a small cell-permeable NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), suppresses expression of proinflammatory cytokines and ameliorates mouse arthritis. It remained unclear, however, whether DHMEQ directly affects osteoclast precursor cells to suppress their differentiation to mature osteoclasts in vivo. The effect of DHMEQ on human osteoclastogenesis also remained elusive. In the present study, we therefore examined the effect of DHMEQ on osteoclastogenesis using a mouse collagen-induced arthritis model, and using culture systems of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis, and of osteoclast precursor cells from peripheral blood of healthy volunteers. DHMEQ significantly suppressed formation of osteoclasts in arthritic joints, and also suppressed expression of NFATc1 along the inner surfaces of bone lacunae and the eroded bone surface, while serum levels of soluble receptor activator of NF-kappaB ligand (RANKL), osteoprotegerin and macrophage colony-stimulating factor were not affected by the treatment. DHMEQ also did not suppress spontaneous expression of RANKL nor of macrophage colony-stimulating factor in culture of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis. These results suggest that DHMEQ suppresses osteoclastogenesis in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL/receptor activator of NF-kappaB/osteoprotegerin cascade, at least in our experimental condition. Furthermore, in the presence of RANKL and macrophage colony-stimulating factor, differentiation and activation of human osteoclasts were also suppressed by DHMEQ, suggesting the possibility of future application of NF-kappaB inhibitors to rheumatoid arthritis therapy.
Arthritis Res Ther 2007
PMID:NF-kappaB inhibitor dehydroxymethylepoxyquinomicin suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANKL, osteoprotegerin or macrophage colony-stimulating factor. 1789

We performed this study to clarify whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, prevents trabecular bone mass reduction by suppressing arthritis-related increase of bone resorption, and to discriminate differences in actions on bone among celecoxib, SC-58560 (a selective COX-1 inhibitor), and indomethacin. Eight-week-old DBA/1J male mice were divided into six groups as follows. Control untreated (Normal) and collagen-induced arthritic (CIA) mice were compared with four treatment groups: celecoxib was orally administered to CIA mice at doses of 0 (Vehicle), 16 (COX2L), and 75 (COX2H) mg/kg, in addition to two groups of mice treated with SC-58560 (COX1) or indomethacin (IND). Histomorphometry showed a significant decrease in tibial trabecular bone volume in arthritic mice, which was corrected by COX2H. The increased osteoclast surface and number in the Vehicle group were suppressed by COX2L, COX2H, and IND. The decreased bone formation rate in Vehicle was elevated by COX2H without statistical significance. A high ratio of mRNA expression of receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) in Vehicle synovial tissue was suppressed by COX2L and COX2H. The increased expression of interleukin (IL)-6 mRNA in Vehicle was suppressed by COX2L, COX2H, and IND, although no difference in this expression was observed in bone marrow cells among all groups. In conclusion, in CIA mice, celecoxib suppresses arthritis-related increase in bone resorption at low and high doses and prevents trabecular bone mass reduction at high doses in association with suppression of osteoclast development in bone marrow through inhibition of RANKL/OPG ratio and IL-6 mRNA expression in inflammatory synovial tissue.
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PMID:Selective cyclooxygenase-2 inhibitor prevents reduction of trabecular bone mass in collagen-induced arthritic mice in association with suppression of RANKL/OPG ratio and IL-6 mRNA expression in synovial tissues but not in bone marrow cells. 1830 70

IL-23, a clinically novel cytokine, targets CD4(+) T cells. Recent IL-1Ra(-/-) mouse studies have demonstrated that IL-23 indirectly stimulates the differentiation of osteoclast precursors by enhancing IL-17 release from CD4(+) T cells. IL-17, in turn, stimulates osteoclastogenesis in osteoclast precursor cells. In this study, we found that IL-23 up-regulates receptor activator of NF-kappaB ligand expression by CD4(+) T cells, and thus contributes to osteoclastogenesis. This indirect pathway is mediated by NF-kappaB and STAT3. We have also demonstrated that IL-23 can influence osteoclastogenesis positively under the special conditions in the IL-1-dominant milieu of IL-1Ra(-/-) mice. We propose that IL-23-enhanced osteoclastogenesis is mediated mainly by CD4(+) T cells. The results of this study show that IL-23 is a promising therapeutic target for the treatment of arthritis-associated bone destruction.
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PMID:IL-23 induces receptor activator of NF-kappaB ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model. 1860 6


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