Matrix metalloproteinase-3–dependent generation of a macrophage chemoattractant in a model of herniated disc resorption
Hirotaka Haro, … , Dan M. Spengler, Lynn M. Matrisian
Hirotaka Haro, … , Dan M. Spengler, Lynn M. Matrisian
Published January 15, 2000
Citation Information: J Clin Invest. 2000;105(2):133-141. https://doi.org/10.1172/JCI7090.
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Article

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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(a) Representative Safranin O–stained section of incubated whole disc ti...
(a) Representative Safranin O–stained section of incubated whole disc tissue. Wild-type whole disc tissue cocultured with peritoneal macrophages (mφ/wt) showed extensive reduction in staining compared with wild-type discs without macrophages (wt) or MMP-3–null whole disc tissue cocultured with macrophages (mφ/3–). ×250. (b) Quantitative analysis of wet weight loss in whole disc tissue from MMP-null organ cultures. Cocultures are indicated by the genotype of the mice donating macrophage/disc tissue. Wild-type discs were also treated with recombinant TNFα (rTNFα) and assayed for MMP-3 protein by Western analysis (inset) and wet weight (wt + rTNFα). Data were analyzed with the Mann-Whitney test and were presented as mean ± SD, n = 7 discs/group. * Difference in wet weight between before and 3 days after incubation is significant (P < 0.01). wt, wild-type; 3–, MMP-3 null; 7–, MMP-7 null.