Carbon Monoxide Inhibits Receptor Activator of NF-κB (RANKL)-Induced Osteoclastogenesis (original) (raw)
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Inflammation, 2009
Carbon monoxide (CO), long considered a toxic gas, has recently been shown to mediate anti-inflammatory effects in various animal models. The aim of this study was to investigate whether the inhalation of CO ameliorated collagen-induced arthritis (CIA) in mice. CIA was induced in female DBA/1 mice by the injection of an anti-type II collagen antibody and lipopolysaccharide. The CO treatment group was exposed to CO gas at a concentration of 200 ppm in a closed cage starting on the day of the injection with an anti-type II collagen antibody and throughout the remaining study period. The clinical arthritis scores was examined daily for swelling of the paws as a sign of arthritis. For histopathology, the sections of the hind legs were evaluated by hematoxylineosin staining. Moreover, we evaluated the expression of interleukin (IL)-1β and monocyte chemoattractant protein-1 (MCP-1) mRNA in the hind paws. Both clinical arthritis scores as well as histological findings of joint inflammation were significantly reduced in mice treated with CO gas inhalation compared to untreated mice. Further, CO significantly inhibited the increased expression of IL-1β and MCP-1 mRNA in paws at day 3 after the induction of arthritis. In conclusion, the inhalation of CO protected mice from the synovial inflammation of CIA. Based on these data, the beneficial effects of CO in murine RA model may be attributed to its anti-inflammatory properties.
BMC Systems Biology, 2014
Background During osteoclastogenesis, the maturation of osteoclast (OC) progenitors is stimulated by the receptor activator of nuclear factor-κB ligand (RANKL). Excess OC production plays a critical role in the pathogenesis of inflammatory bone disorders. Conversely, the inhibition of abnormal OC proliferation reduces inflammation-induced bone loss. Low concentrations of carbon monoxide (CO) are known to decrease inflammation and OC-mediated bone erosion but the molecular mechanism is unknown. Results To obtain insight into the biological function of CO, cultured RANKL-treated RAW 264.7 cells were used in an in vitro experimental model of osteoclastogenesis. The results showed that CO inhibited: 1) tartrate-resistant acid phosphatase (TRAP)-positive cell formation; 2) F-actin ring production; 3) c-fos pathway activation; 4) the expression of cathepsin K, TRAP, calcitonin receptor, and matrix metalloproteinase-9 mRNAs; 5) the expression of nuclear factor of activated T cells, cytopla...
Journal of Interferon & Cytokine Research, 2013
Cigarette smoking is a major established environmental risk factor for rheumatoid arthritis (RA), and synoviocyte-derived proinflammatory cytokines are implicated in the pathogenesis of RA. We have reported that aryl hydrocarbon or cigarette smoke condensate (CSC) is able to upregulate the production of proinflammatory cytokines from an RA patient-derived synovial fibroblast cell line MH7A. In this study, we compared the effect of CSC on induction of interleukin-1b (IL-1b) from RA or osteoarthritis (OA) patient-derived synovial fibroblasts, and studied the mechanism of the effect of CSC. CSC induced IL-1b mRNA from RA patient-derived synoviocytes and MH7A, but not from OA patient-derived synoviocytes. CSC induced the mRNA and both precursor and mature forms of IL-1b, and caspase-1 activity in MH7A. The mechanism of CSC-induced IL-1b mRNA expression was investigated in MH7A. Reporter gene analyses and promoter pull-down assay indicated that 3 novel NF-kB sites at -3771 to -3762 bp, -3105 to -3096 bp, and -2787 to -2778 bp in the promoter region of the IL-1b gene, especially the far distal NF-kB site and NF-kB activation, are critical for the gene activation by CSC. CSC-induced NF-kB activation, IL-1b promoter activity, IL-1b mRNA upregulation, and CYP1A1 mRNA induction were all inhibited by an aryl hydrocarbon receptor (AhR) antagonist a-naphthoflavone. These results indicate that CSC induced IL-1b production from RA patient-derived synoviocytes, but not OA patient-derived synoviocytes, through AhR-dependent NF-kB activation and novel NF-kB sites.
Journal of Autoimmunity, 2012
Bone destruction is a common feature of inflammatory arthritis and is mediated by osteoclasts, the only specialized cells to carry out bone resorption. Aberrant expression of receptor activator of nuclear factor kappa b ligand (RANKL), an inducer of osteoclast differentiation has been linked with bone pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this manuscript, we challenge the current concept that an increase in RANKL expression governs osteoclastogenesis and bone destruction in autoimmune arthritis.
The Journal of rheumatology, 2003
OBJECTIVE Transgenic mice that express human tumor necrosis factor-alpha (Tg197 h-TNF-alpha) develop polyarthritis at 3 to 4 weeks of age leading to severe joint destruction at 8 to 10 weeks of age. Studies have suggested that inducible nitric oxide synthase (iNOS) activity can modulate the progression of arthritis. We investigated the induction of iNOS together with argininosuccinate synthase (AS) and GTP cyclohydrolase I (GTPCH), 2 of the rate-limiting enzymes for high output NO generation, in the Tg197 h-TNF-alpha transgenic model of arthritis. METHODS We used 4 and 8-week-old Tg197 h-TNF-alpha transgenic mice and wild-type CBA C57B1/6 control mice to investigate the expression of iNOS with respect to that of AS, GTPCH, and 3-nitrotyrosine by quantitative RT-PCR and immunocytochemistry. Urinary NO metabolites were analyzed using a chemiluminescence assay. RESULTS Inducible NOS, AS, and GTPCH mRNA was found in all study groups; however, only iNOS mRNA showed a clear increase in 4-...
Antioxidants
A relationship between carbon monoxide (CO) and hydrogen sulfide (H2S) has been described in different pathological conditions, but their interaction in modulating joint pain has not yet been investigated. In young female mice with monosodium acetate-induced joint degeneration and pain, we assessed: (1) the effects of CORM-2 (tricarbonyldichlororuthenium(II)dimer), a CO-releasing molecule, and CoPP (cobalt protoporphyrin IX), an inducer of heme oxygenase 1 (HO-1), administered alone and combined with low doses of two slow-releasing H2S donors, DADS (diallyl disulfide) and GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex) on the mechanical allodynia and loss of grip strength provoked by joint degeneration; (2) the role of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 in the antinociceptive actions of H2S donors; (3) the impact of DADS and GYY4137 treatment on the expression of Nrf2 and several antioxidant proteins in dorsal roo...
British Journal of Pharmacology, 2009
Background and purpose:Recent evidence indicates that carbon monoxide‐releasing molecules (CO‐RMs) exhibit potential anti‐inflammatory properties. In the present study, we have investigated whether tricarbonyl dichloro ruthenium(II) dimer (CORM‐2) can control the inflammatory response induced by cytokines in a human colonic epithelial cell line, Caco‐2.Experimental approach:Caco‐2 cells were preincubated with CORM‐2 for 30 minutes and then stimulated with interleukin (IL)‐1β, tumor necrosis factor‐α and interferon‐γ for different times. Gene expression was analyzed by real‐time PCR. Protein expression was investigated by Western blot and ELISA. Transcription factor activation was determined by the luciferase method.Key results:We have shown that CORM‐2 significantly decreased the mRNA expression of nitric oxide synthase‐2 (NOS‐2) and the production of nitrite, in Caco‐2 cells stimulated with cytokines. IL‐8, IL‐6 and metalloproteinase‐7 (MMP‐7) mRNA and protein were also significant...
Journal of Cellular Biochemistry, 2007
4-hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues and was recently identified as a potent catabolic factor in OA cartilage. In this study, we provide additional evidence that HNE acts as an inflammatory mediator by elucidating the signaling cascades targeted in OA chondrocytes leading to cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression. HNE induced COX-2 protein and mRNA levels with accompanying increases in prostaglandin E2 (PGE 2 ) production. In contrast, HNE had no effect on basal iNOS expression or nitric oxide (NO) release. However, HNE strongly inhibited IL-1b-induced iNOS or NO production. Transient transfection experiments revealed that the ATF/CRE site (À58/À53) is essential for HNE-induced COX-2 promoter activation and indeed HNE induced ATF-2 and CREB-1 phosphorylation as well as ATF/CRE binding activity. Overexpression of p38 MAPK enhanced the HNE-induced ATF/CRE luciferase reporter plasmid activation, COX-2 synthesis and promoter activity. HNE abrogated IL-1b-induced iNOS expression and promoter activity mainly through NF-kB site (À5,817/À5,808) possibly via suppression of IKKa-induced IkBa phosphorylation and NF-kB/p65 nuclear translocation. Upon examination of upstream signaling components, we found that IKKa was inactivated through HNE/ IKKa adduct formation. Taken together, these findings illustrate the central role played by HNE in the regulation of COX-2 and iNOS in OA. The aldehyde induced selectively COX-2 expression via ATF/CRE activation and inhibited iNOS via IKKa inactivation.
Psychopharmacology, 2014
Rationale Carbon monoxide synthetized by inducible heme oxygenase (HO-1) exerts potent anti-inflammatory and antinociceptive effects during acute and neuropathic pain, but its role in the modulation of chronic inflammatory pain and the possible involvement of nitric oxide in this action remain unknown. Objectives and methods The antiallodynic and antihyperalgesic effects of a carbon monoxide releasing molecule, tricarbonyldichlororuthenium(II) dimer (CORM-2), daily administered from days 4 to 14 after complete Freund's adjuvant (CFA) injection in wild-type (WT), neuronal (NOS1-KO), and inducible (NOS2-KO) nitric oxide synthases knockout mice, were evaluated using von Frey filaments and plantar tests. Effects of CORM-2 treatment on the expression of HO-1, NOS1, and NOS2 at 14 days after inflammation induction were assessed by Western blot. Results Main inflammatory pain symptoms induced by CFA in WT, NOS1-KO, and NOS2-KO mice were significantly reduced in a time-dependent manner by CORM-2 treatment. In all genotypes, inflammation increased the dorsal root ganglia and paw expression of HO-1, but CORM-2 treatment only over-expressed this enzyme in the paw of all genotypes. The increased NOS1 expression induced by inflammation in WT mice was abolished by CORM-2 treatment, while there was no effect of the inflammation in neither CORM-2 treatment in the expression of NOS2 in WT and NOS1-KO mice. Conclusions CORM-2 treatment inhibits inflammatory pain through enhancing HO-1 paw expression in all genotypes and reducing NOS1 over-expression in WT mice. An interaction between HO-1/carbon monoxide and NOS1/nitric oxide systems was also demonstrated. CORM-2 treatment may represent a new approach for management chronic inflammatory pain.
Suppression of arthritis by an inhibitor of nitric oxide synthase
The Journal of experimental medicine, 1993
Nitric oxide (NO), a toxic radical gas produced during the metabolism of L-arginine by NO synthase (NOS), has been implicated as a mediator of immune and inflammatory responses. A single injection of streptococcal cell wall fragments (SCW) induces the accumulation of inflammatory cells within the synovial tissue and a cell-mediated immune response that leads destructive lesions. We show here that NO production is elevated in the inflamed joints of SCW-treated rats. Administration of NG-monomethyl-L-arginine, an inhibitor of NOS, profoundly reduced the synovial inflammation and tissue damage as measured by an articular index and reflected in the histopathology. These studies implicate the NO pathway in the pathogenesis of an inflammatory arthritis and demonstrate the ability of a NOS inhibitor to modulate the disease.