Interleukin-1β upregulates MMP-9 expression in stromal cells of human giant cell tumor of bone

Velidi H. Rao, Rakesh K. Singh, Duane C. Delimont, G. Bradley Schaefer, Julia A. Bridge, James R. Neff, Warren G. Sanger, Joshua W. Sappenfield, Bruce A. Buehler, Richard H. Finnell

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Giant cell tumor (GCT) of bone is a progressive, potentially malignant process that destroys skeletal tissue. It consists of multinucleated giant cells, which are hypothesized to be derived from a monocyte/macrophage lineage and mononuclear stromal cells, and the precise relationship of these cells is not fully understood. Recently, we demonstrated that the production of matrix metalloproteinase-9 (MMP-9) in GCT stromal cells is regulated by certain factor(s) secreted by the multinucleated giant cells. In the present study, we evaluated for the presence of interleukin-1β (IL-1β) and attempted to establish its possible role for the induction of MMP-9 in GCT stromal cells. Using enzyme-linked immunosorbent assay (ELISA), we have demonstrated that the primary GCT cultures secrete both IL-1β and MMP-9. The addition of monoclonal antibody (mAb) against IL-1β partially abrogated, but did not abolish, MMP-9 expression. Our results on gelatin zymography, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunofluorescence showed that GCT stromal cells did not express MMP-9, although treatment with IL-1β induced MMP-9 expression in a dose-dependent manner, and the secretion peaked 24 h after stimulation and then plateaued. Studies with cycloheximide, a protein synthesis inhibitor, demonstrated that de novo protein synthesis is required for IL-1β induced MMP-9 expression. Moreover, nuclear run-on analysis has revealed that IL-1β significantly increased MMP-9 gene transcription in GCT stromal cells. The data suggest that IL-1β secreted by the multinucleated giant cells in GCT may be one of the factors responsible for the induction of MMP-9 at the transcriptional level in GCT stromal cells in vivo. We conclude that GCT has a self-stimulatory system for the production of MMP-9, and the ability of stromal cells to produce MMP-9 with appropriate stimuli, such as IL-1β, and possibly in concert with other cytokines may contribute to the aggressive and potentially malignant behavior of GCT.

Original languageEnglish (US)
Pages (from-to)1207-1217
Number of pages11
JournalJournal of Interferon and Cytokine Research
Volume19
Issue number10
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Immunology
  • Cell Biology
  • Virology

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