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Role of Interleukin 6 (IL-6)/IL-6R-Induced Signal Tranducers and
Activators of Transcription and Mitogen-Activated Protein Kinase/Extracellular
Signal-Related Kinase in Upregulation of Matrix Metalloproteinase
and ADAMTS Gene Expression in Articular Chondrocytes
FLORENCE LEGENDRE, PATRICK BOGDANOWICZ, KARIM BOUMEDIENE, and JEAN-PIERRE PUJOL ABSTRACT. 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. Conclusion. 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. (J Rheumatol 2005;32:1307-16) Key Indexing Terms: INTERLEUKIN 6 From the Laboratory of Connective Tissue Biochemistry, Faculty of Medicine, University of Caen, Caen, France. F. Legendre, PhD; P. Bogdanowicz, PhD; K. Boumédiène, PhD; J-P. Pujol, PhD, Professor, University of Caen. Address reprint requests to Prof. J-P. Pujol, Laboratory of Connective Tissue Biochemistry, Faculty of Medicine, 14032 Caen Cedex, France. E-mail : pujol@ibfa.unicaen.fr Accepted for publication February 2, 2005. |