Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.
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PMID:Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases. 1846 3

Celecoxib is a specific inhibitor of cyclooxygenase 2 (COX2). While it has been used for the treatment of chronic inflammatory conditions, including rheumatoid arthritis, its detailed anti-inflammatory mechanism has not been clarified. Here, we found that Celecoxib potently inhibited TNFalpha-induced transcriptional activity and DNA binding activity of NF-kappaB; however, Celecoxib had no effect on TNFalpha-induced IKK activation and degradation of IkappaBalpha and IkappaBbeta, suggesting that it inhibited NF-kappaB activation via suppressing downstream of IKK activation and IkappaBs degradation. Interestingly, it was also found that Celecoxib abrogated TNFalpha-induced nuclear accumulation of the NF-kappaB p65 subunit. As a result, TNFalpha-induced expression of inflammatory cytokines, CXCL1/KC and CCL2/MCP-1, was clearly inhibited by Celecoxib. On the other hand, Celecoxib had no effect on the TNFalpha-induced nuclear translocation of c-jun and activation of ERK, JNK, p38 and Akt. Taken together, these data indicate that Celecoxib specifically inhibits TNFalpha-induced NF-kappaB activation at the level of its nuclear translocation. This negative regulation of NF-kappaB activation by Celecoxib might be an important mechanism leading to its anti-inflammatory activity.
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PMID:Celecoxib potently inhibits TNFalpha-induced nuclear translocation and activation of NF-kappaB. 1864 47

Osteoclasts are multinucleated cells with the unique ability to resorb bone. Elevated activity of these cells under pathologic conditions leads to the progression of bone erosion that occurs in osteoporosis, periodontal disease, and rheumatoid arthritis. Thus, the regulation of osteoclast apoptosis is important for bone homeostasis. In this study, we examined the effects of the Janus tyrosine kinase 2 specific inhibitor AG490 on osteoclast apoptosis. We found that AG490 greatly inhibited osteoclast apoptosis. AG490 stimulated the phosphorylation of Akt and ERK. Adenovirus-mediated expression of dominant negative (DN)-Akt and DN-Ras in osteoclasts inhibited the survival of osteoclasts despite the presence of AG490. Cytochrome c release during osteoclast apoptosis was inhibited by AG490 treatment, but this effect was inhibited in the presence of LY294002 or U0126. AG490 suppressed the proapoptotic proteins Bad and Bim, which was inhibited in osteoclasts infected with DN-Akt and DN-Ras adenovirus. In addition, constitutively active MEK and myristoylated-Akt adenovirus suppressed the cleavage of pro-caspase-9 and -3 and inhibited osteoclast apoptosis induced by etoposide. Taken together, our results suggest that AG490 inhibited cytochrome c release into the cytosol at least partly by inhibiting the pro-apoptotic proteins Bad and Bim, which in turn suppressed caspase-9 and -3 activation, thereby inhibiting osteoclast apoptosis.
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PMID:AG490, a Jak2-specific inhibitor, induces osteoclast survival by activating the Akt and ERK signaling pathways. 1869 55

Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neurodegenerative disorders. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a terminal dehydration product of prostaglandin D(2), is an endogenous ligand of peroxisome proliferator-activated receptor-gamma and exhibits a number of biological activities including the proapoptotic activity. Recent studies have revealed that this cyclopentenone prostaglandin, at non-toxic concentrations, can also exert antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of 15d-PGJ(2) on the H2O2-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H2O2 underwent apoptosis, which was attenuated by pretreatment with non-toxic concentrations of 15d-PGJ(2). Treatment of the PC12 cells with 15d-PGJ(2) resulted in increased nuclear translocation, DNA-binding and transcriptional activity of NF-E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1) expression, which provided an adaptive survival response against the H2O2-derived oxidative cytotoxicity. Transfection of PC12 cells with dominant-negative Nrf2 gene abolished the 15d-PGJ(2)-derived induction of HO-1 expression. Moreover, the 15d-PGJ(2)-mediated increases in Nrf2-ARE binding and ARE luciferase activity were suppressed by the dominant-negative mutation as well as the pharmacological inhibition of Akt/protein kinase B or extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings suggest that 15d-PGJ(2) augments cellular antioxidant defense capacity through activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from H2O2-induced oxidative cell death.
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PMID:15-Deoxy-Delta(12,14)-prostaglandin J(2) rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: potential roles of Akt and ERK1/2. 1877 81

It has been recently demonstrated that small gold compounds could have a potential anti-tumoral activity. Here, we report that aurothiomalate (ATM), a gold compound already used in clinical therapy for the treatment of rheumatoid arthritis, has a pro-apoptotic effect in aggressive prostate cancer (PC3U) cells. In contrast, treatment of human primary epithelial prostate cells (PrEC) with ATM did not cause apoptosis. We demonstrated that ATM is able to disrupt the PKCiota-Par6 complex in PC3U cells and that this disruption leads to the activation of ERK in a dose-dependent manner. Interestingly, we also showed that ERK acts upstream of the activation of caspase 3, leading to apoptosis. ATM treatment also causes activation of p38 and JNK MAP kinases. Moreover we could link ATM treatment to activation of the mitochondrial or so called intrinsic pathway, as we observed release of cytochrome c from mitochondria to cytoplasm, suggesting that the mitochondrial pathway is involved in the pro-apoptotic effect mediated by ATM. Taken together our data suggest that ATM could be a new promising drug for the treatment of advanced prostate cancer.
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PMID:Pro-apoptotic effect of aurothiomalate in prostate cancer cells. 1916 22

Mizoribine is a disease-modifying anti-rheumatic drug (DMARD) that is used in the treatment of rheumatoid arthritis. However, clinical use of the drug is restricted to a few Asian countries due to a lack of comprehensive evidence on its effectiveness. The inhibitory effect of the drug on human osteoclastogenesis was investigated in the hopes of providing some clear evidence. Mizoribine was found to inhibit in vitro osteoclastogenesis in a dose-dependent manner. In addition, the size of the pit area was closely related to the number of osteoclasts in a bone resorption assay. However, mizoribine did not affect the phosphorylation of MAP kinase (p38, JNK, ERK), the degradation of IkappaBalpha, or receptor activator of NF-kappaB ligand (RANKL) expression in fibroblast-like synoviocytes stimulated with IL-1beta. These results suggested that mizoribine may partially suppress osteoclastogenesis, leading to progressive bone erosion by inhibiting the growth or the signaling pathway of precursor cells to form osteoclasts rather than fibroblast-like synoviocytes.
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PMID:Mizoribine may suppress bone erosion in patients with rheumatoid arthritis by inhibiting osteoclastogenesis. 1917 Nov 30

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
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PMID:Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production. 1921 82

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was originally described to induce apoptosis specifically in cancer cells, but not in normal cells. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients exhibit tumor-like features and we have described earlier that TRAIL induces apoptosis only in a subset of RA FLS, but an induction of proliferation in the surviving cells. This observation corresponds to the pleiotropic effects of TRAIL observed on primary human tumor cells. Here, we describe that the PI3 kinase/Akt-signaling pathway, but not that of the MAP kinases ERK and p38, protects RA FLS from TRAIL-induced apoptosis by modulating the expression of the cell survival regulators p21, XIAP, Mcl-1 and RIP. Moreover, we found that not only TRAIL-induced apoptosis, but also TRAIL-triggered proliferation in RA FLS is mediated by caspases with a crucial role for caspase 8. TRAIL was found to induce degradation of p21 and p27 that was caspase-dependent, but independent of the ERK, p38 and PI3 kinase/Akt-signaling pathways. The finding that TRAIL-triggered proliferation and apoptosis share intracellular routes has to be taken in consideration in defining therapeutic strategies on the basis of the administration of TRAIL.
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PMID:The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases. 1940 27

Regulation of matrix metalloproteinase-13 (MMP-13) by collagen matrix in the synovial fibroblasts of rheumatoid arthritis (RA) is critical event in the progressive joint destruction. Our previous study indicated that a collagen receptor, discoidin receptor 2 (DDR2), was highly expressed in the synovial fibroblasts of RA. However, the functional role of DDR2 in the regulation of MMP-13 production in synovial fibroblasts has not been elucidated. In this study, we initially demonstrated that the DDR2 and MMP-13 proteins are both highly expressed in the synovial lining layer of RA. MMP-13 mRNA and protein in synovial fibroblasts of RA were preferentially induced by collagen type II compared with MMP-1. Furthermore, stable overexpression of wild type DDR2 in murine synoviocytes dramatically augments the production of MMP-13. The activation of DDR2 also mediates the up-regulation of MMP-13 promoter activity in 293T cells. Inhibitor specific for extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) cascade was shown to decrease MMP-13 level induced by collagen II in RA synovial fibroblasts and DDR2-induced MMP-13 promoter activity. Runx2 and activator protein-1 (AP-1) binding sites in MMP-13 promoter region are required for DDR2-induced transcription. The data in this study suggest that DDR2-mediated MMP-13 induction by collagen matrix in synovial fibroblasts of RA contributed to articular cartilage destruction.
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PMID:Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis. 1941 60

Fibroblast-like synovial cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA), as these cells are involved in inflammation and joint destruction. Apigenin, a dietary plant-flavonoid, is known to have many functions in animal cells including anti-proliferative and anticancer activities, but its role in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) has not been reported. In this study, we investigated the roles of apigenin in RA-FLSs. The survival rate decreased, and apoptotic cell death was induced by apigenin treatment in RA-FLSs. Apigenin treatment resulted in activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and pretreatment with an ERK inhibitor PD98059 dramatically reduced apigenin-induced apoptosis. We found that apigenin-mediated production of a large amount of intracellular reactive oxygen species (ROS) caused activation of ERK1/2 and apoptosis; treatment with the antioxidant Tiron strongly inhibited the apigenin-induced generation of ROS, phosphorylation of ERK1/2, and apoptotic cell death. Apigenin-induced apoptotic cell death was mediated through activation of the effectors caspase-3 and caspase-7, and was blocked by pretreatment with Z-VAD-FMK (a pan-caspase inhibitor). These results showed that apigenin-induced ROS and oxidative stress-activated ERK1/2 caused apoptotic cell death in apigenin-treated RA-FLSs.
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PMID:Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 in rheumatoid fibroblast-like synoviocytes. 1964 29


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