Abstract
Giant Cell Tumor of bone (GCT) is an aggressively osteolytic and cytokine-rich bone tumor. Previous work in our lab has shown that matrix metalloproteinase-13 (MMP-13) is the principal proteinase expressed by the mesenchymal stromal cells of GCT. The Runx2 transcription factor is known to have a binding site in the MMP-13 promoter region, and we have previously found this transcription factor to be constitutively expressed in GCT stromal cells. The purpose of this study was to determine the role of Runx2 in MMP-13 regulation in GCT stromal cells. Following in vitro stimulation of GCT stromal cells with incremental concentrations of cytokine IL-1beta or TNF-alpha, the level of MMP-13 mRNA expression increased dramatically over 100-fold with a concomitant increase in MMP-13 protein expression. Inhibition of the ERK and JNK signaling pathways inhibited the upregulation of MMP-13 in these cells. Runx2 siRNA knockdown resulted in MMP-13 knockdown, and this effect was amplified following cytokine stimulation. Our study provides the first evidence that Runx2 may play a crucial role in cytokine-mediated MMP-13 expression in GCT stromal cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Core Binding Factor Alpha 1 Subunit / metabolism*
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Culture Media, Conditioned
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Enzyme Induction / drug effects
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Neoplastic* / drug effects
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Gene Knockdown Techniques
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Giant Cell Tumor of Bone / enzymology*
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Giant Cell Tumor of Bone / genetics*
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Giant Cell Tumor of Bone / pathology
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Humans
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Immunohistochemistry
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Interleukin-1beta / pharmacology
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Matrix Metalloproteinase 13 / genetics*
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Matrix Metalloproteinase 13 / metabolism
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Matrix Metalloproteinase 2 / metabolism
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Stromal Cells / drug effects
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Stromal Cells / enzymology
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Stromal Cells / metabolism*
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Stromal Cells / pathology
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Up-Regulation / drug effects
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Up-Regulation / genetics*
Substances
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Core Binding Factor Alpha 1 Subunit
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Culture Media, Conditioned
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Interleukin-1beta
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Protein Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase 2