title: Interleukin-1 induction of aggrecanase gene expression in human articular chondrocytes is mediated by mitogen-activated protein kinases.
abstract: OBJECTIVE
  We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And Metalloproteinase with ThromboSpondin motifs) in human articular chondrocytes, a model mimicking human arthritis.
  
  
  METHODS
  Chondrocytes were pretreated with various pharmacological inhibitors and then stimulated with IL-1β for 24 h. ADAMTS-4 expression or activity was studied by RT-PCR or ELISA and other proteins measured by Western blotting.
  
  
  RESULTS
  MAP kinase kinase-specific inhibitor, U0126 inhibited IL-1-induced phosphorylation of ERK1/2 and down-regulated ADAMTS-4 expression and activity. Protein 38 inhibitor, SB203580 down-regulated the phosphorylation of p38 and its target, activating transcription factor-2 (ATF-2), ADAMTS-4 mRNA and activity. C-Jun N-terminal kinase (JNK) inhibitor, SP600125 diminished IL-1-stimulated JNK phosphorylation, ADAMTS-4 mRNA expression and enzyme activity. A c-fos/lipoxygenase pathway inhibitor and antioxidant, nordihydroguaiaretic acid (NDGA) significantly suppressed ADAMTS-4 mRNA induction and activity. Activating protein (AP-1) and nuclear factor kappa B (NF-ĸB) transcription factor inhibitors, curcumin and pyrrolidine dithiocarbamate (PDTC) partially inhibited ADAMTS-4 induction and activity.
  
  
  CONCLUSIONS
  These results suggest partial involvement of ERK-, p38-and JNK-MAPKs as well as AP-1, ATF-2 and NF-ĸB transcription factors in IL-1-induced ADAMTS-4 in chondrocytes. Inhibition of these targets by the specific pharmacological agents could be useful for reducing aggrecanase-driven cartilage resorption in arthritis.
authors: Département de Médecine, Université de Montréal and Centre de recherche du CHUM (CRCHUM)-Hôpital Notre-Dame, 1560 Sherbrooke E, Montreal Québec, Canada.
authors: Judith
authors: J
authors: Sylvester
authors: Mohammed
authors: M
authors: El Mabrouk
authors: Rasheed
authors: R
authors: Ahmad
authors: Ataf
authors: A
authors: Chaudry
authors: Muhammad
authors: M
authors: Zafarullah
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D003474:Curcumin / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058945:Lipoxygenases / Q000737:chemistry / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D053583:Interleukin-1beta; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; C113580:U 0126; C432165:pyrazolanthrone; C020972:pyrrolidine dithiocarbamic acid; D009637:Masoprocol; D058945:Lipoxygenases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010450:Endopeptidases; C083641:aggrecanase; D003474:Curcumin; C093642:SB 203580