Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption

J Clin Invest. 2000 Jan;105(2):133-41. doi: 10.1172/JCI7090.


Herniated disc (HD) is a common health problem that is resolved by surgery unless spontaneous resorption occurs. HD tissue contains abundant macrophage infiltration and high levels of matrix metalloproteinases (MMPs) MMP-3 and MMP-7. We developed a model system in which disc tissue or isolated chondrocytes from wild-type or MMP-null mice were cocultured with peritoneal macrophages and used this system to investigate the role of MMPs and chondrocyte/macrophage interactions in disc resorption. We observed a marked enhancement of MMP-3 protein and mRNA in chondrocytes after exposure to macrophages. Chondrocytic MMP-3, but not MMP-7, was required for disc resorption, as determined by assaying for a reduction in wet weight and proteoglycan content after 3 days of coculture. Surprisingly, chondrocyte MMP-3 was required for the generation of a macrophage chemoattractant and the subsequent infiltration of the disc tissue by proteolytically active macrophages. We conclude that macrophage induction of chondrocyte MMP-3 plays a major role in disc resorption by mechanisms that include the generation of a bioactive macrophage chemoattractant.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Migration Inhibition
  • Chondrocytes / cytology
  • Chondrocytes / enzymology
  • Coculture Techniques
  • Culture Media, Conditioned / pharmacology
  • Diffusion Chambers, Culture
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Intervertebral Disc / cytology
  • Intervertebral Disc / drug effects
  • Intervertebral Disc / enzymology
  • Intervertebral Disc Displacement / enzymology*
  • Intervertebral Disc Displacement / genetics
  • Intervertebral Disc Displacement / pathology
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / enzymology*
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism*
  • Matrix Metalloproteinase 7 / genetics
  • Matrix Metalloproteinase 7 / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Organ Culture Techniques
  • RNA, Messenger / metabolism
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • Culture Media, Conditioned
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 7