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.
Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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.
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PMID: 10642591 [PubMed - indexed for MEDLINE]PMCID: PMC377425