The inhibitory effect and the molecular mechanism of glabridin on RANKL-induced             osteoclastogenesis in RAW264.7 cells.
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.
Department of Biomedical Science, College of Health Science,                     Korea University, Seoul 136-703, Republic of Korea.
Hyun-Sook
HS
Kim
Kwang Sik
KS
Suh
Donggeun
D
Sul
Byung-Jo
BJ
Kim
Seung Kwan
SK
Lee
Woon-Won
WW
Jung
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D000081247:CSK Tyrosine-Protein Kinase; D024402:Carbonic Anhydrase II / Q000235:genetics / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007529:Isoflavones / Q000494:pharmacology*; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D000081247:CSK Tyrosine-Protein Kinase; D024402:Carbonic Anhydrase II; D056657:Cathepsin K; D018118:Chloride Channels; D007529:Isoflavones; D048688:MAP Kinase Kinase 7; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D025262:Vacuolar Proton-Translocating ATPases; D019061:src-Family Kinases; C484226:Atp6ap1 protein, mouse; C490803:Clcn7 protein, mouse; C490894:Gab2 protein, mouse; C509143:OSTM1 protein, mouse; C482570:Map2k7 protein, mouse; C107601:glabridin