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https://ir.cnu.edu.tw/handle/310902800/27879
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| 標題: | KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-kappa B and Calcium/Calcineurin/NFATc1 Pathways |
| 作者: | Liou, Shu-Fen
Hsu, Jong-Hau
Lin, I-Ling
Ho, Mei-Ling
Hsu, Pei-Chuan
Chen, Li-Wen
Chen, Ing-Jun
Yeh, Jwu-Lai |
| 貢獻者: | 藥學系 |
| 關鍵字: | Receptor Activator
Smooth-Muscle
K+ Channels
Cyclic-Gmp
Phosphodiesterase-4 Inhibitor
Cardiac-Hypertrophy
Signal-Transduction
Down-Regulation
Differentiation
Cells |
| 日期: | 2013-07 |
| 上傳時間: | 2014-05-26 10:47:23 (UTC+8) |
| 出版者: | Public Library Science |
| 摘要: | Background: KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.Principal Findings: In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1 beta, IL-6, TNF-alpha and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-kappa B), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.Conclusions: KMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis. |
| 關聯: | Plos One, v.8 n.7, e69468 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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