Abstract
Regulation of receptor activator of nuclear factor kappaB-ligand (RANKL)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. We identified the inhibitory effects of cantharidin on RANKL-induced differentiation and bone resorptive activities of osteoclasts in macrophage-like RAW264.7 cells. Interestingly, cantharidin significantly inhibited RANKL-induced ERK/MAP kinase activation and protein phosphatase 2A (PP2A) activity. In addition, cantharidin significantly inhibited RANKL-induced mRNA expression of transcription factors and osteoclast-specific genes (especially Fra-2 and cathepsin K, respectively). Although further studies might be required to elucidate the precise mechanism of cantharidin's action on osteoclast differentiation and bone resorptive activities, our results suggested that cantharidin-mediated inactivation of PP2A could prevent RANKLinduced activation of ERK/MAP kinase and transcription factors such as AP-1 and NFATc1, with subsequent inhibition of osteoclast-specific gene expression required for efficient osteoclast differentiation and bone resorption.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Density Conservation Agents / pharmacology*
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Bone Resorption / genetics
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Bone Resorption / metabolism
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Bone Resorption / pathology
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Bone Resorption / prevention & control*
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Cantharidin / pharmacology*
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Cathepsin K / metabolism
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Cell Differentiation / drug effects*
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Cell Differentiation / genetics
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Cell Line
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fos-Related Antigen-2 / genetics
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Gene Expression Regulation / drug effects
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Mice
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NFATC Transcription Factors / genetics
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Osteoclasts / drug effects*
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Phosphorylation
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Protein Phosphatase 2 / antagonists & inhibitors
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Protein Phosphatase 2 / metabolism
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RANK Ligand / metabolism
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RNA, Messenger / metabolism
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Transcription Factor AP-1 / genetics
Substances
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Bone Density Conservation Agents
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Enzyme Inhibitors
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Fos-Related Antigen-2
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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RANK Ligand
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RNA, Messenger
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Transcription Factor AP-1
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Extracellular Signal-Regulated MAP Kinases
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Protein Phosphatase 2
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Cathepsin K
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Ctsk protein, mouse
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Cantharidin