Abstract
Osteoblastic bone formation and osteoclastic bone resorption are in balance to maintain a constant, homeostatically controlled amount of bone. Excessive bone resorption by osteoclasts is involved in the pathogenesis of bone-related disorders. In the present study, we evaluated the inhibitory effects of glabridin, a flavonoid purified from licorice root, on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and its molecular mechanisms in murine osteoclast progenitor RAW264.7 cells. Glabridin significantly inhibited RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity, the formation of multinucleated osteoclasts and resorption-pit formation. In mechanistic studies of the anti-osteoclastogenic potential of glabridin, we found that glabridin inhibited RANKL-induced expression of c-Fos and subsequent expression of NFATc1, which is a master regulator of osteoclastogenesis. Interestingly, glabridin inhibited the RANKL-induced expression of signaling molecules (TRAF6, GAB2, ERK2, JNK1 and MKK7) and osteoclast survival-related signaling pathways such as c-Src, PI3K and Akt2. Glabridin also inhibited the bone resorptive activity of mature osteoclasts by inhibiting osteoclast-associated genes (cathepsin K, MMP-9, CAII, TCIRG1, OSTM1 and CLCN7). Taken together, our data suggest that glabridin holds great promise for use in preventing osteoclastogenesis by inhibiting RANKL-induced activation of signaling molecules and subsequent transcription factors in osteoclast precursors and these findings may be useful for evaluating treatment options in bone-destructive diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Bone Resorption / genetics
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CSK Tyrosine-Protein Kinase
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Carbonic Anhydrase II / genetics
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Carbonic Anhydrase II / metabolism
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Cathepsin K / genetics
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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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Cells, Cultured
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Chloride Channels / genetics
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Chloride Channels / metabolism
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Gene Expression Regulation / drug effects
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Isoflavones / pharmacology*
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MAP Kinase Kinase 7 / genetics
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MAP Kinase Kinase 7 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / 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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Phenols / pharmacology*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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RANK Ligand / antagonists & inhibitors*
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RANK Ligand / metabolism
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Vacuolar Proton-Translocating ATPases / genetics
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Vacuolar Proton-Translocating ATPases / metabolism
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src-Family Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Atp6ap1 protein, mouse
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Chloride Channels
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Clcn7 protein, mouse
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Gab2 protein, mouse
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Isoflavones
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Membrane Proteins
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NFATC Transcription Factors
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OSTM1 protein, mouse
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Phenols
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Phosphoproteins
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Proto-Oncogene Proteins c-fos
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RANK Ligand
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TNF Receptor-Associated Factor 6
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 7
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Map2k7 protein, mouse
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Cathepsin K
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Matrix Metalloproteinase 9
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Vacuolar Proton-Translocating ATPases
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Carbonic Anhydrase II
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glabridin