Naringin-induced bone morphogenetic protein-2 expression via PI3K, Akt, c-Fos/c-Jun and AP-1 pathway in osteoblasts.
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.
Wu
Jin-Bin
JB
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Fong
Yi-Chin
YC
Tsai
Huei-Yann
HY
Chen
Yuh-Fung
YF
Tsuzuki
Minoru
M
Tang
Chih-Hsin
CH
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044950:Flavanones / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics*
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D044950:Flavanones; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C005274:naringin