Role of interleukin 6 (IL-6)/IL-6R-induced signal tranducers and activators of transcription and mitogen-activated protein kinase/extracellular.
OBJECTIVE
Studies have described elevated levels of interleukin 6 (IL-6) and its soluble receptor (sIL-6R) in osteoarthritic and rheumatoid joints, as well as the inhibitory effect of this combination on cartilage matrix production. We investigated the ability of IL-6/sIL-6R to modulate gene expression of matrix metalloproteinase (MMP) and ADAMTS (ADAMS with thrombospondin motifs) family members in bovine chondrocytes, and the potential role of signal transducers and activators of transcription (STAT) and mitogen-activated protein kinases (MAPK) in this regulation.


METHODS
Primary cultures of bovine chondrocytes were stimulated with IL-6/sIL-6R for 30 min (Western blot and EMSA) or 24 h (RNA measurements) in the presence or absence of the STAT inhibitor parthenolide or the MAPK inhibitor PD 098059. mRNA was assessed by RT-PCR for the expression of MMP (MMP-1, -3, and -13) and 2 ADAMT family members (ADAMTS-4 and -5/11).


RESULTS
IL-6/sIL-6R markedly induced activation of STAT and extracellular signal-related kinase (ERK1/2) and the subsequent expression of the collagenases MMP-1 and MMP-13 as well as MMP-3, an aggrecan-degrading enzyme and activator of pro-MMP. Expression of the 2 specific aggrecanases ADAMTS-4 and -5/11 was also elevated by this combination. Both STAT and MAPK signaling pathways were found to contribute to the IL-6/sIL-6R induction mechanisms, the overall effect being dependent on the respective magnitude of response and the crosstalk between the 2 pathways.


CONCLUSIONS
These data indicate that the cartilage-degrading properties of IL-6/sIL-6R are mediated by induction of the aggrecan-degrading enzymes ADAMTS-4, -5/11, and MMP-3, and the collagen-degrading enzymes MMP-1 and -13. STAT and MAPK pathways play a crucial role in IL-6/sIL-6R modulation of these enzymes, suggesting that new strategies in the treatment of osteoarticular diseases might target these transduction cascades.
Legendre
Florence
F
Laboratory of Connective Tissue Biochemistry, Faculty of Medicine, University of Caen, Caen, France.
Bogdanowicz
Patrick
P
Boumediene
Karim
K
Pujol
Jean-Pierre
JP
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011348:Procollagen N-Endopeptidase; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D015534:Trans-Activators; C002669:parthenolide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051722:ADAM Proteins; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000071121:ADAMTS4 Protein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one