Inhibition of interleukin-1beta-induced activation of MEK/ERK pathway and DNA binding of NF-kappaB and AP-1: potential mechanism for Diacerein effects in osteoarthritis.
In the present report we have shown that bovine articular chondrocytes cultured in low oxygen tension, i.e. in conditions mimicking their hypoxic in vivo environment, respond to IL-1beta (10 ng/ml) by an increased DNA binding activity of NF-kappaB and AP-l transcription factors. Incubation of the cells with 10(-5) M Rhein, the active metabolite of Diacerhein, for 24 h was found to reduce this activity particularly in the case of AP-1. Mitogen activated kinases (ERK-1 and ERK-2) were activated by exposure of the chondrocytes to a 1 h treatment with IL-1beta. This effect was greater in hypoxia (3% O2) than in normoxia (21% O2). Rhein was capable of reducing the IL-1beta-stimulated ERK1/ERK2 pathway whatever the tension of oxygen present in the environment. The mRNA steady-state levels of collagen type II (COL2A1) and aggrecan core protein were found to be significantly increased by a 24-h treatment with 10(-5) M Rhein. This stimulating effect was also observed in the presence of IL-1beta, suggesting that the drug could prevent or reduce the IL-1beta-induced inhibition of extra cellular matrix synthesis. IL-1-induced collagenase (MMP1) expression was significantly decreased by Rhein under the same conditions. In conclusion, Rhein can effectively inhibit the IL-1-activated MAPK pathway and the binding of NF-kappaB and AP-1 transcription factors, two key factors involved in the expression of several pro-inflammatory genes by chondrocytes. In addition, the drug can reduce the procatabolic effect of the cytokine, by reducing the MMP1 synthesis, and enhance the synthesis of matrix components, such as type II collagen and aggrecan. These results may explain the anti-osteoarthritic properties of Rhein and its disease-modifying effects on OA cartilage, in spite of the absence of inhibition at prostaglandin level.
Domagala
F
F
Laboratoire Negma-Lerads, Toussus-le-Noble, Magny-les-Hameaux Cedex, France. f.domagala@negma-lerads.fr
Martin
G
G
Bogdanowicz
P
P
Ficheux
H
H
Pujol
J-P
JP
D053674:Aggrecans; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology* / Q000378:metabolism; D002417:Cattle; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
D053674:Aggrecans; D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011508:Chondroitin Sulfate Proteoglycans; D024043:Collagen Type II; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; C025292:diacerein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017364:Collagenases; C020491:rhein