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Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice

Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice
Lee, JW[Lee, Ji-Won]Kobayashi, Y[Kobayashi, Yasuhiro]Nakamichi, Y[Nakamichi, Yuko]Udagawa, N[Udagawa, Nobuyuki]Takahashi, N[Takahashi, Naoyuki]Im, NK[Im, Nam-Kyung]Seo, HJ[Seo, Hwa-Jeong]Jeon, WB[Jeon, Won Bae]Yonezawa, T[Yonezawa, Takayuki]Cha, BY[Cha, Byung-Yoon]Woo, JT[Woo, Je-Tae]
DGIST Authors
Seo, HJ[Seo, Hwa-Jeong]; Jeon, WB[Jeon, Won Bae]
Issue Date
Biochemical Pharmacology, 80(3), 352-361
Article Type
2 Methylene 19 NorcalcitriolActinAlismaAlisma OrientaleAlisol-BAnimal CellAnimal ExperimentAnimal ModelAnimal TissueAnimalsAnti-Resorptive AgentBone Marrow CellBone ResorptionCalcitriolCalcitriol DerivativeCell CultureCell DifferentiationCell FunctionCholestenonesCoculture TechniquesColony Stimulating Factor 1Controlled StudyEnzyme PhosphorylationHumansHypercalcemiaIn Vitro StudyIn Vivo StudyJanus KinaseJNKMacrophageMaleMessenger RNAMiceMice, Inbred C57BLMouseNewbornNon-HumanOsteoblastOsteoclastOsteoclast Differentiation FactorOsteoclastogenesisOsteoclastsOsteogenesisOsteolysisPhytosteroidPriority JournalProtein C FosProtein ExpressionProtein NFATc1RANK LigandRANKLReceptor Activator of Nuclear Factor Kappa BReverse Transcriptase-Polymerase Chain ReactionStem CellSteroidSteroidsTranscription FactorUnclassified DrugUpregulation
Osteoclasts, bone-resorbing multinucleated cells, are differentiated from hemopoietic progenitors of the monocyte/macrophage lineage. Bone resorption by osteoclasts is considered a potential therapeutic target to the treatment of erosive bone diseases, including osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we found that alisol-B, a phyto-steroid from Alisma orientale Juzepczuk, exhibited inhibitory effects on osteoclastogenesis both in vitro and in vivo. Although RT-PCR analysis showed that alisol-B did not affect the 1α,25(OH)2D3-induced expressions of RANKL, OPG and M-CSF mRNAs in osteoblasts, addition of alisol-B to co-cultures of mouse bone marrow cells and primary osteoblasts with 10-8M 1α,25(OH)2D3 caused significant inhibition of osteoclastogenesis. We further examined the direct effects of alisol-B on osteoclast precursors. Alisol-B strongly inhibited RANKL-induced osteoclast formation when added during the early stage of cultures, suggesting that alisol-B acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, alisol-B inhibited the phosphorylation of JNK, which are upregulated in response to RANKL in bone marrow macrophages, alisol-B also inhibited RANKL-induced expression of NFATc1 and c-Fos, which are key transcription factors for osteoclastogenesis. In addition, alisol-B suppressed the pit-forming activity and disrupted the actin ring formation of mature osteoclasts. In a hypercalcemic mouse model induced by 2-methylene-19-nor-(20S)-1α,25(OH)2D3 (2MD), an analog of 1α,25(OH)2D3, administration of alisol-B significantly suppressed 2MD-induced hypercalcemia as resulting from the inhibition of osteoclastogenesis. Taken together, these findings suggest that alisol-B may be a potential novel therapeutic molecule for bone disorders by targeting the differentiation of osteoclasts as well as their functions. © 2010.
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