論文 - 詳細
| RRC ID | 17695 |
|---|---|
| 著者 | Yonezawa T, Hasegawa S, Asai M, Ninomiya T, Sasaki T, Cha BY, Teruya T, Ozawa H, Yagasaki K, Nagai K, Woo JT. |
| タイトル | Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo. |
| ジャーナル | Eur J Pharmacol |
| Abstract |
Bone homeostasis is controlled by the balance between osteoblastic bone formation and osteoclastic bone resorption. Excessive bone resorption is involved in the pathogenesis of bone-related disorders such as osteoporosis, arthritis and periodontitis. To obtain new antiresorptive agents, we searched for natural compounds that can inhibit osteoclast differentiation and function. We found that harmine, a β-carboline alkaloid, inhibited multinucleated osteoclast formation induced by receptor activator of nuclear factor-κB ligand (RANKL) in RAW264.7 cells. Similar results were obtained in cultures of bone marrow macrophages supplemented with macrophage colony-stimulating factor and RANKL, as well as in cocultures of bone marrow cells and osteoblastic UAMS-32 cells in the presence of vitamin D(3) and prostaglandin E(2). Furthermore, harmine prevented RANKL-induced bone resorption in both cell and bone tissue cultures. Treatment with harmine (10 mg/kg/day) also prevented bone loss in ovariectomized osteoporosis model mice. Structure-activity relationship studies showed that the C3-C4 double bond and 7-methoxy group of harmine are important for its inhibitory activity on osteoclast differentiation. In mechanistic studies, we found that harmine inhibited the RANKL-induced expression of c-Fos and subsequent expression of nuclear factor of activated T cells (NFAT) c1, which is a master regulator of osteoclastogenesis. However, harmine did not affect early signaling molecules such as ERK, p38 MAPK and IκBα. These results indicate that harmine inhibits osteoclast formation via downregulation of c-Fos and NFATc1 induced by RANKL and represses bone resorption. These novel findings may be useful for the treatment of bone-destructive diseases. |
| 巻・号 | 650(2-3) |
| ページ | 511-8 |
| 公開日 | 2011-1-15 |
| DOI | 10.1016/j.ejphar.2010.10.048 |
| PII | S0014-2999(10)01075-7 |
| PMID | 21047508 |
| MeSH | Animals Bone Marrow Cells / metabolism Bone Resorption / drug therapy Bone Resorption / pathology* Cell Differentiation / drug effects* Cells, Cultured Coculture Techniques Down-Regulation Female Harmine / chemistry Harmine / pharmacology* Macrophage Colony-Stimulating Factor / metabolism Mice Mice, Inbred ICR NFATC Transcription Factors / metabolism Osteoblasts / drug effects Osteoblasts / metabolism Osteoclasts / drug effects* Osteoclasts / physiology Ovariectomy RANK Ligand / metabolism Signal Transduction Structure-Activity Relationship |
| IF | 3.263 |
| 引用数 | 27 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | RAW 264(RCB0535) |