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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 Norcalcitriol; Actin; Alisma; Alisma Orientale; Alisol-B; Animal Cell; Animal Experiment; Animal Model; Animal Tissue; Animals; Anti-Resorptive Agent; Bone Marrow Cell; Bone Resorption; Calcitriol; Calcitriol Derivative; Cell Culture; Cell Differentiation; Cell Function; Cholestenones; Coculture Techniques; Colony Stimulating Factor 1; Controlled Study; Enzyme Phosphorylation; Humans; Hypercalcemia; In Vitro Study; In Vivo Study; Janus Kinase; JNK; Macrophage; Male; Messenger RNA; Mice; Mice, Inbred C57BL; Mouse; Newborn; Non-Human; Osteoblast; Osteoclast; Osteoclast Differentiation Factor; Osteoclastogenesis; Osteoclasts; Osteogenesis; Osteolysis; Phytosteroid; Priority Journal; Protein C Fos; Protein Expression; Protein NFATc1; RANK Ligand; RANKL; Receptor Activator of Nuclear Factor Kappa B; Reverse Transcriptase-Polymerase Chain Reaction; Stem Cell; Steroid; Steroids; Transcription Factor; Unclassified Drug; Upregulation
- 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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