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KMID : 1007320090150010024
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Journal of the Korean Society of Menopause
2009 Volume.15 No. 1 p.24 ~ p.34
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The Mechanism of Alendronate Action during Osteoblast Proliferation and Differentiation
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Kim Heung-Yeol
Eo Wan-Kyu
Jung Min-Hyung
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Abstract
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Objectives: To investigate the effect of alendronate on osteoblast proliferation and differentiation using the mouse myoblastic cell line, C2C12.
Methods: C2C12 cell lines were cultured in DMEM media with various concentrations (10?9 M, 10?8 M, 10?7 M, 10?6 M, 10?5 M, 10?4 M) of alendronate for one, two, or three days. After the indicated culture times, MTT assay and ALP activity were examined. The expression of genes for ALP, osteocalcin (OCN), collagen I ?1 (Col 1), inhibitor of differentiation (Id), and cathepsin K (CTSK) were examined using RT-PCR. Transcription factors related to the increased expression of Id genes were identified with the TRANSFEC program. The effects of these transcription factors on the expression of Id genes were tested using a promoter assay.
Results: Alendronate had no cytotoxicity, regardless of the concentration used. ALP activity in C2C12 cells was increased in the alendronate-treated group compared to the control group before 24 hours of treatment, but decreased rapidly after 24 hours of treatment. ALP, Col 1, and OCN gene expression tended to increase with decreasing alendronate concentrations before 24 hours of treatment in both cell lines. Id-1 gene expression began to increase from 10?6 M of alendronate compared to the control group, and continued to increase to 10?8 M. Id?2 gene expression increased gradually with increasing alendronate concentrations. Among the transcription factors related to the promoter of the Id genes, CREB and C/EBP? increased the promoter activity of Id genes 2-fold and 4-fold, respectively. Co-treatment with C/EBP? and alendronate resulted in significantly increased promoter activity in the Id genes compared to treatment with each by itself.
Conclusion: Alendronate has a dose-dependent effect in osteoblast differentiation. The effect may be associated with increased expression of the Id genes via a synergistic interaction with C/EBP?.
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KEYWORD
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Bisphosphonates, Alendronate, Osteoblasts, Inhibitor of differentiation proteins, C/EBP?
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