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

Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM, Matrisian LM
J Clin Invest. 2000 105 (2): 143-50

PMID: 10642592 · PMCID: PMC377426 · DOI:10.1172/JCI7091

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-alpha from peritoneal macrophages. The generation of soluble TNF-alpha 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-alpha 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.

MeSH Terms (17)

Animals Bone Resorption Cell Migration Inhibition Cells, Cultured Coculture Techniques Diffusion Chambers, Culture Disease Models, Animal Enzyme Induction Intervertebral Disc Intervertebral Disc Displacement Macrophages, Peritoneal Matrix Metalloproteinase 3 Matrix Metalloproteinase 7 Mice Mice, Inbred Strains Mice, Knockout Tumor Necrosis Factor-alpha

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