| 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
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
