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Matrix metalloproteinase-7–dependent release of tumor necrosis factor-α 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):143-150. https://doi.org/10.1172/JCI7091.
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Article

Matrix metalloproteinase-7–dependent release of tumor necrosis factor-α in a model of herniated disc resorption

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Abstract

Herniated disc (HD), one of the major causes of low back pain, is often resolved spontaneously without surgical intervention. Resorption is associated with a marked increase in infiltrating macrophages, and the matrix metalloproteinases (MMP) MMP-3 and MMP-7 have been implicated in this phenomenon. We developed a murine organ culture model in which intact intervertebral discs were cocultured with peritoneal macrophages to investigate the role of MMPs in HD resorption. Using macrophages isolated from MMP-null mice, we report that macrophage-produced MMP-7 was required for proteoglycan degradation, loss of wet weight, and macrophage infiltration of cocultured discs. The inability of MMP-7–deficient macrophages to infiltrate discs could not be attributed to a defect in macrophage migration. MMP-7 was required for the release of the cytokine TNF-α from peritoneal macrophages. The generation of soluble TNF-α was essential for the induction of MMP-3 in disc cocultures, which in turn is required for the generation of a macrophage chemoattractant and subsequent macrophage infiltration. TNF-α release from macrophages was necessary but insufficient for disc resorption, which required macrophage infiltration. We conclude that there is extensive communication between macrophages and chondrocytes in HD resorption and that an essential component of this communication is the requirement for MMPs to release soluble bioactive factors.

Authors

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

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Figure 2

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Quantitative analysis of macrophage infiltration in MMP-null organ cultu...
Quantitative analysis of macrophage infiltration in MMP-null organ cultures. Macrophages from wild-type or MMP-null mice were cocultured with wild-type disc tissue. The genotype of the mice donating macrophages/disc tissue is indicated. wt = wild-type; 3– = MMP-3–null, 7– = MMP-7–null tissue. In a representative experiment, whole disc tissue was divided into 3 regions: nucleus pulposus (NP; inner gelatinous region), annulus fibrosus (AF; outer layer), and transition zone (TZ; intermediate layer), and the number of PKH26-labeled red fluorescent macrophages in 3 high-power fields in each region was determined. Data were analyzed with the Kruskal-Wallis test and were presented as mean ± SD. *Statistically significant difference (P < 0.05) compared with wild-type.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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