Matrix metalloproteinase-3–dependent generation of a macrophage chemoattractant in a model of herniated disc resorption
Hirotaka Haro, Howard C. Crawford, Barbara Fingleton, John R. MacDougall, Kenichi Shinomiya, Dan M. Spengler, Lynn M. Matrisian
Hirotaka Haro, Howard C. Crawford, Barbara Fingleton, John R. MacDougall, Kenichi Shinomiya, Dan M. Spengler, Lynn M. Matrisian
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Matrix metalloproteinase-3–dependent generation of a macrophage chemoattractant in a model of herniated disc resorption

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.

Authors

Hirotaka Haro, Howard C. Crawford, Barbara Fingleton, John R. MacDougall, Kenichi Shinomiya, Dan M. Spengler, Lynn M. Matrisian

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Quantitative analysis of macrophage infiltration in MMP-null organ cultu...
Quantitative analysis of macrophage infiltration in MMP-null organ cultures. A representative experiment showing the number of PKH26-labeled red fluorescent–infiltrated peritoneal macrophages in 3 high-power fields per zone of cocultured discs from wild-type (wt) and MMP-null mice (7–, MMP-7–null; 3–, MMP-3–null) is depicted. Cocultures are indicated by the genotype of the mice donating macrophages/disc tissue. Whole disc tissue was classified into 3 zones, NP (inner gelatinous region), AF (outer layer), and transition zone (TZ; intermediate layer). Data were analyzed with the Kruskal-Wallis test and were presented as mean ± SD. *Difference from wild-type is significant (P < 0.05).