The Carbon Monoxide-Releasing Molecule Tricarbonyldichlororuthenium(II) Dimer Protects Human Osteoarthritic Chondrocytes and Cartilage from the Catabolic Actions of Interleukin-1β

Megías, Javier; Guillén, Marı́a Isabel; Brú, Antonio; Gomar, F.; Alcaraz, Marı́a José

doi:10.1124/jpet.107.134650

Cited by 21 publications

(16 citation statements)

References 37 publications

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“…Moreover, CO may decrease both ROS and NO production in osteoarthritic chondrocytes stimulated by IL-1β [37]. This was associated to a weak expression of MMP-1, MMP-3, MMP-10 and MMP-13 [42]. In our study, we showed that CO reduces Nox4 activity.…”

Section: Discussionsupporting

confidence: 53%

Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes

et al. 2013

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Interleukin-1β (IL-1β) activates the production of reactive oxygen species (ROS) and secretion of MMPs as well as chondrocyte apoptosis. Those events lead to matrix breakdown and are key features of osteoarthritis (OA). We confirmed that in human C-20/A4 chondrocytes the NADPH oxidase Nox4 is the main source of ROS upon IL-1β stimulation. Since heme molecules are essential for the NADPH oxidase maturation and activity, we therefore investigated the consequences of the modulation of Heme oxygenase-1 (HO-1), the limiting enzyme in heme catabolism, on the IL-1β signaling pathway and more specifically on Nox4 activity. Induction of HO-1 expression decreased dramatically Nox4 activity in C-20/A4 and HEK293 T-REx™ Nox4 cell lines. Unexpectedly, this decrease was not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. In fact, the inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, led to a confinement of the Nox4/p22phox heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. Therefore, the downregulation of Nox4 activity by HO-1 induction appeared to be mediated by carbon monoxide (CO) generated from the heme degradation process. Interestingly, either HO-1 or CO caused a significant decrease in the expression of MMP-1 and DNA fragmentation of chondrocytes stimulated by IL-1β. These results all together suggest that a modulation of Nox4 activity via heme oxygenase-1 may represent a promising therapeutic tool in osteoarthritis.

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Section: Discussionsupporting

confidence: 53%

Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes

et al. 2013

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“…These molecules have been shown to be effective in a wide range of animal models, including pancreatitis, hepatic ischemia-reperfusion, colitis, cutaneous wound healing, neuropathic pain and osteoarthritis [98]. Like NO and H 2 S, CO can suppress leukocyte adherence to the vascular endothelium and reduce pro-inflammatory cytokine expression by inhibiting NF-B [100][101][102][103]. Also in line with the actions of the other two major gaseous mediators, CO has been shown to exert particularly potent protective effects in the GI tract [104].…”

Section: Carbon Monoxidementioning

confidence: 99%

Gaseous mediators in resolution of inflammation

Wallace

Ianaro

Flannigan

2015

Seminars in Immunology

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“…Recently, CO-releasing molecules (CO-RMs) have been synthesized as a new drug class able to reproduce many of the biological effects of HO and CO [8], [9]. We have shown previously that CORM-3 exerts anti-arthritic effects in mice [10] and CORM-2 reduces the production of some inflammatory mediators and MMPs in OA chondrocytes [11], [12]. However, evidence to show whether CO-RMs are capable of modulating the metabolism of OA synoviocytes is lacking.…”

Section: Introductionmentioning

confidence: 99%

Control of Cell Migration and Inflammatory Mediators Production by CORM-2 in Osteoarthritic Synoviocytes

et al. 2011

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BackgroundOsteoarthritis (OA) is the most widespread degenerative joint disease. Inflamed synovial cells contribute to the release of inflammatory and catabolic mediators during OA leading to destruction of articular tissues. We have shown previously that CO-releasing molecules exert anti-inflammatory effects in animal models and OA chondrocytes. We have studied the ability of CORM-2 to modify the migration of human OA synoviocytes and the production of chemokines and other mediators sustaining inflammatory and catabolic processes in the OA joint.Methodology/Principal FindingsOA synoviocytes were stimulated with interleukin(IL)-1β in the absence or presence of CORM-2. Migration assay was performed using transwell chambers. Gene expression was analyzed by quantitative PCR and protein expression by Western Blot and ELISA. CORM-2 reduced the proliferation and migration of OA synoviocytes, the expression of IL-8, CCL2, CCL20, matrix metalloproteinase(MMP)-1 and MMP-3, and the production of oxidative stress. We found that CORM-2 reduced the phosphorylation of extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase1/2 and to a lesser extent p38. Our results also showed that CORM-2 significantly decreased the activation of nuclear factor-κB and activator protein-1 regulating the transcription of chemokines and MMPs in OA synoviocytes.Conclusion/SignificanceA number of synoviocyte functions relevant in OA synovitis and articular degradation can be down-regulated by CORM-2. These results support the interest of this class of agents for the development of novel therapeutic strategies in inflammatory and degenerative conditions.

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The Carbon Monoxide-Releasing Molecule Tricarbonyldichlororuthenium(II) Dimer Protects Human Osteoarthritic Chondrocytes and Cartilage from the Catabolic Actions of Interleukin-1β

Cited by 21 publications

References 37 publications

Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes

Heme Oxygenase-1 Regulates Matrix Metalloproteinase MMP-1 Secretion and Chondrocyte Cell Death via Nox4 NADPH Oxidase Activity in Chondrocytes

Gaseous mediators in resolution of inflammation

Control of Cell Migration and Inflammatory Mediators Production by CORM-2 in Osteoarthritic Synoviocytes

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