Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes.
Interleukin (IL)-17 promotes cartilage breakdown by inducing matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motif, ADAMTS) in arthritic joints. We investigated IL-17 signaling pathways inducing MMP-3, MMP-13 and ADAM-TS4 genes in bovine articular chondrocytes. IL-17 stimulated phosphorylation of extracellular signal-regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK). ERK pathway inhibitors, PD98059 and U0126, down-regulated IL-17-induced MMP and ADAM-TS4 gene expression. Protein 38 and JNK pathway inhibitors, SB203580 and SP600125, also reduced induction of these genes. Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes. Similarly, nuclear factor kappa B (NF-kappaB) pathways inhibitors curcumin and Bay-11-7085 also blocked their induction. Thus MMP-3, MMP-13 and ADAM-TS4 genes are coordinately up-regulated by IL-17 via MAP kinases, activating protein-1 (AP-1) and NF-kappaB mediators, which could be targeted for reducing IL-17-triggered cartilage damage.
Sylvester
Judith
J
Research Center, CHUM Hôpital Notre-Dame, K-5255 Mailloux, 1560 Sherbrooke est, Montréal, Québec, Canada H2L 4M1.
Liacini
Abdelhamid
A
Li
Wen Qing
WQ
Zafarullah
Muhammad
M
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D009637:Masoprocol / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011348:Procollagen N-Endopeptidase; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000111:Acetylcysteine; D017364:Collagenases; D003474:Curcumin; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D048031:JNK Mitogen-Activated Protein Kinases; D009637:Masoprocol; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases; D020928:Mitogen-Activated Protein Kinases; D011348:Procollagen N-Endopeptidase; D017346:Protein Serine-Threonine Kinases; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C507079:MMP13 protein, human