The Xanthine Derivative KMUP-1 Inhibits RANKL-induced Osteoclastogenesis and Bone Loss in Ovariectomized Animal Model

• Main Authors: Li-Wen Chen, 陳俐妏
• Other Authors: Jwu-Lai Yeh
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/74839115579229918391

碩士 === 高雄醫學大學 === 藥理學研究所 === 99 === Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodonitis, and rheumatoid arthritis. Inhibition of osteoclast differentiation and bone resorption is considered as an effective therapeutic approach in the treatment of bone loss. Recently, phosphodiesterase (PDE) 4 inhibitors have been shown to have therapeutic effects in different experimental osteopenia models. The effect of KMUP-1, a PDE inhibitor, in M-CSF (macrophage colony-stimulating factor) and receptor activator of nuclear factor kappa B (RANKL)-induced osteoclast differentiation was examined in this study. In vitro, we found that KMUP-1 inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) of mice in a dose-dependent manner without any evidence of cytotoxicity and attenuated the bone resorption activity of differentiated osteoclasts. KMUP-1 also suppressed the MAP kinases, NF-κB, PI3K/Akt signaling pathways and the induction of c-fos and NFATc1 during osteoclastogenesis. We further investigated the effects of KMUP-1 on ovariectomy-induced bone loss using Micro-CT and serum markers assay for bone remodeling. Mice treated with KMUP-1 demonstrated attenuation of bone erosion based on Micro-CT and biochemical markers of bone turnover. These results collectively suggested that KMUP-1 demonstrated inhibitory effects on osteoclast differentiation in vitro, and suppressed ovariectomy-induced bone loss in vivo. Thus, KMUP-1 may serve as a therapeutic drug in the prevention of bone loss.