Naringin-induced bone morphogenetic protein-2 expression via PI3K, Akt, c-Fos/c-Jun and AP-1 pathway in osteoblasts

被引:120
作者
Wu, Jin-Bin [2 ,6 ]
Fong, Yi-Chin [3 ]
Tsai, Huei-Yann [4 ,6 ]
Chen, Yuh-Fung [5 ]
Tsuzuki, Minoru [6 ]
Tang, Chih-Hsin [1 ]
机构
[1] China Med Univ, Dept Pharmacol, Coll Med, Taichung, Taiwan
[2] China Med Univ, Grad Inst Pharmaceut Chem, Taichung, Taiwan
[3] China Med Univ Hosp, Dept Orthopaed, Taichung, Taiwan
[4] China Med Univ, Sch Pharm, Taichung, Taiwan
[5] China Med Univ, Grad Inst Chinese Pharmaceut Sci, Coll Pharm, Taichung, Taiwan
[6] China Med Univ, Tsuzuki Inst Tradit Med, Taichung, Taiwan
关键词
naringin; osteoblast; osteoporosis; flavonoid; BMP-2;
D O I
10.1016/j.ejphar.2008.04.030
中图分类号
R9 [药学];
学科分类号
1007 [药学];
摘要
Osteoporosis is a reduction in skeletal mass due to an imbalance between bone resorption and bone formation. Bone morphogenetic protein (BMP) plays important roles in osteoblastic differentiation and bone formation. Therefore, components involved in BMP activation are good targets for the development of anti-osteoporosis drugs. In this study, naringin a polymethoxylated flavonoid, was shown to enhance alkaline phosphatase activity, osteocalcin level, osteopontin synthesis and cell proliferation in primary cultured osteoblasts. Naringin increased mRNA and protein levels of BMP-2 using Western blot, ELISA and RT-PCR assay. In addition, naringin also prevented the decreasing of BMP-2 and bone loss inducing by ovariectomy in vivo. The transcriptional regulation of BMP-2 by naringin was mediated by phosphorylation of Akt and activation of the activator protein-1 (AP-1) components c-Fos and c-Jun. The binding of c-Fos and c-Jun to the AP-1 element on the BMP-2 promoter was enhanced by naringin. Transfection with dominant-negative mutant of p85 and Akt or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of naringin on BMP-2 production. Taken together, our results provide evidence that naringin increase BMP-2 expression and enhance osteogenic response via the phosphoinositide 3-kinase (PI3K), Akt, c-Fos/c-Jun and AP-1-dependent signaling pathway. (C) 2008 Elsevier B.V. All rights reserved.
引用
收藏
页码:333 / 341
页数:9
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