Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice
| Autor: | Naoyuki Takahashi, Yuko Nakamichi, Nobuyuki Udagawa, Yasuhiro Kobayashi, Je-Tae Woo, Hwa-Jeong Seo, Won Bae Jeon, Byung-Yoon Cha, Nam-Kyung Im, Ji-Won Lee, Takayuki Yonezawa |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty medicine.medical_treatment Osteoclasts Biochemistry Bone resorption Mice Multinucleate Osteogenesis Osteoclast Internal medicine medicine Animals Humans Bone Resorption Cholestenones Pharmacology biology business.industry Monocyte RANK Ligand Coculture Techniques Mice Inbred C57BL Endocrinology medicine.anatomical_structure Cytokine RANKL biology.protein Cancer research Steroids Tumor necrosis factor alpha Bone marrow business |
| Zdroj: | Biochemical Pharmacology. 80:352-361 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2010.04.014 |
| Popis: | 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 1alpha,25(OH)(2)D(3)-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(-8)M 1alpha,25(OH)(2)D(3) 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)-1alpha,25(OH)(2)D(3) (2MD), an analog of 1alpha,25(OH)(2)D(3), 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. |
| Databáze: | OpenAIRE |
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