Abstract
Receptor activator NF-kappaB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation and survival. Caffeic acid phenethyl ester (CAPE), a natural NF-kappaB inhibitor from honeybee propolis has been shown to have anti-tumor and anti-inflammatory properties. In this study, we investigated the effect of CAPE on the regulation of RANKL-induced osteoclastogenesis, bone resorption and signaling pathways. Low concentrations of CAPE (<1 microM) dose dependently inhibited RANKL-induced osteoclastogenesis in RAW264.7 cell and bone marrow macrophage (BMM) cultures, as well as decreasing the capacity of human osteoclasts to resorb bone. CAPE inhibited both constitutive and RANKL-induced NF-kappaB and NFAT activation, concomitant with delayed IkappaBalpha degradation and inhibition of p65 nuclear translocation. At higher concentrations, CAPE induced apoptosis and caspase 3 activities of RAW264.7 and disrupts the microtubule network in osteoclast like (OCL) cells. Taken together, our findings demonstrate that inhibition of NF-kappaB and NFAT activation by CAPE results in the attenuation of osteoclastogenesis and bone resorption, implying that CAPE is a potential treatment for osteolytic bone diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / metabolism
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Active Transport, Cell Nucleus / drug effects
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Animals
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Apoptosis / drug effects
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Bone Resorption / pathology*
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Caffeic Acids / administration & dosage
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Caffeic Acids / pharmacology*
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Caspase 3 / metabolism
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cells, Cultured
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Humans
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I-kappa B Proteins / metabolism
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Isoenzymes / metabolism
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Macrophages / cytology
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Macrophages / drug effects
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Mice
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Mice, Inbred C57BL
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism*
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Osteoclasts / cytology*
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Osteoclasts / drug effects
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Osteoclasts / metabolism
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Phenylethyl Alcohol / analogs & derivatives
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Propolis / chemistry
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RANK Ligand / pharmacology*
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Tartrate-Resistant Acid Phosphatase
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Transcription Factor RelA / metabolism
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Tumor Cells, Cultured
Substances
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Caffeic Acids
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I-kappa B Proteins
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Isoenzymes
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NF-kappa B
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NFATC Transcription Factors
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NFKBIA protein, human
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Nfkbia protein, mouse
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RANK Ligand
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Rela protein, mouse
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Tnfsf11 protein, mouse
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Transcription Factor RelA
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NF-KappaB Inhibitor alpha
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Propolis
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Casp3 protein, mouse
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Caspase 3
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caffeic acid phenethyl ester
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Phenylethyl Alcohol