Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes

Matrix Biol. 2002 Apr;21(3):251-62. doi: 10.1016/s0945-053x(02)00007-0.

Abstract

Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46-53% (MMP-3) and 59-66% (MMP-13) inhibition of RNA induction in human OA and 47-52% (MMP-3) and 69-73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37-77% (MMP-3) and 43-73% (MMP-13) suppression in human and 77-100% (MMP-3) and 96-100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35-37% reduction of MMP-3 and MMP-13 RNA in human and 36-46% (MMP-3) and 60-88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-kappa B, curcumin, achieved 48-99% suppression of MMP-3 and 45-97% of MMP-13 in human and 8-100% (MMP-3) and 32-100% (MMP-13) in bovine chondrocytes. NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54-64% for MMP-3 and 74-93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage, Articular / cytology
  • Cattle
  • Cells, Cultured
  • Chondrocytes / cytology
  • Chondrocytes / drug effects
  • Chondrocytes / immunology
  • Collagenases / genetics*
  • Curcumin / pharmacology
  • Down-Regulation*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Femur Head / cytology
  • Femur Head / immunology
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-1 / pharmacology*
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3 / genetics*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • Osteoarthritis, Hip / enzymology*
  • Osteoarthritis, Hip / immunology
  • Osteoarthritis, Hip / pathology
  • Pyridines / pharmacology
  • Pyrrolidines / pharmacology
  • Thiocarbamates / pharmacology
  • Time Factors
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-1
  • NF-kappa B
  • Pyridines
  • Pyrrolidines
  • Thiocarbamates
  • Transcription Factor AP-1
  • pyrrolidine dithiocarbamic acid
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3
  • Curcumin
  • SB 203580