Pro-MMP-9 is a specific macrophage product and is activated by osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP-13 cascade

Exp Cell Res. 2004 Jul 15;297(2):303-12. doi: 10.1016/j.yexcr.2004.02.027.


In joint diseases of both the inflammatory (rheumatoid arthritis, or RA) or the degenerative variety (osteoarthritis, or OA), matrix metalloproteinases (MMPs) are essential mediators of irreversible tissue destruction. MMP-9 is secreted as a stable, inactive zymogen and is proteolytically converted to the active enzyme. To understand the activation mechanism of MMP-9 in joint diseases, the process was investigated in serum-free cocultures of human articular chondrocytes and macrophages. Macrophages extensively expressed and secreted pro-MMP-9 whereas chondrocytes failed to produce the enzyme. However, efficient activation of pro-MMP-9 required soluble and membrane-associated chondrocyte proteinases. Two alternative activation pathways mainly involved MMPs and, marginally, serine or cysteine proteinases. MT1-MMP (MMP-14), the only MT-MMP expressed in chondrocytes, converted pro-MMP-13 which, in turn, cleaved pro-MMP-9. Alternatively, pro-MMP-9 was activated less efficiently by MMP-3, which was converted by autocatalysis or by serine or cysteine proteinases. Both pathways were triggered by chondrocytes from OA, but not normal joints. Therefore, articular chondrocytes are not innocent bystanders in joint diseases. They not only produce destructive enzymes guided by environmental cues but also they can instruct inflammatory cells or cells from surrounding tissues to do so by converting in several ways zymogens produced but not activated by these cells themselves.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cartilage, Articular / cytology
  • Cartilage, Articular / metabolism
  • Cells, Cultured
  • Chondrocytes / cytology
  • Chondrocytes / metabolism*
  • Coculture Techniques
  • Collagenases / metabolism
  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • Cysteine Endopeptidases / metabolism
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation
  • Humans
  • Macrophage Activation
  • Macrophages / cytology
  • Macrophages / enzymology*
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3 / metabolism*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism
  • Models, Biological
  • Monocytes / cytology
  • Osteoarthritis / enzymology*
  • Osteoarthritis / pathology
  • Serine Endopeptidases / metabolism


  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • Enzyme Precursors
  • Serine Endopeptidases
  • Cysteine Endopeptidases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 9