Chia Nan University of Pharmacy & Science Institutional Repository:Item 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
    K+ Channels
    Phosphodiesterase-4 Inhibitor
    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.
    显示于类别:[藥學系(所)] 期刊論文


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