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

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

Research output: Contribution to journalArticle

297 Scopus citations

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 MMP3 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.

Original languageEnglish (US)
Pages (from-to)143-150
Number of pages8
JournalJournal of Clinical Investigation
Volume105
Issue number2
DOIs
StatePublished - Jan 2000
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Haro, H., Crawford, H. C., Fingleton, B., Shinomiya, K., Spengler, D. M., & Matrisian, L. M. (2000). Matrix metalloproteinase-7-dependent release of tumor necrosis factor-α in a model of herniated disc resorption. Journal of Clinical Investigation, 105(2), 143-150. https://doi.org/10.1172/JCI7091