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

Haro H, Crawford HC, Fingleton B, MacDougall JR, Shinomiya K, Spengler DM, Matrisian LM
J Clin Invest. 2000 105 (2): 133-41

PMID: 10642591 · PMCID: PMC377425 · 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.

MeSH Terms (23)

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

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