Abstract
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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Migration Inhibition
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Chondrocytes / cytology
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Chondrocytes / enzymology
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Diffusion Chambers, Culture
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Intervertebral Disc / cytology
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Intervertebral Disc / drug effects
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Intervertebral Disc / enzymology
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Intervertebral Disc Displacement / enzymology*
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Intervertebral Disc Displacement / genetics
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Intervertebral Disc Displacement / pathology
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Macrophages, Peritoneal / cytology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / enzymology*
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / metabolism*
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Matrix Metalloproteinase 7 / genetics
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Matrix Metalloproteinase 7 / metabolism
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Organ Culture Techniques
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RNA, Messenger / metabolism
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation
Substances
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Culture Media, Conditioned
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 7