Strait Karen, Li Yan, Dillehay Dirck L, Weitzmann M Neale
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Int J Mol Med. 2008 Apr;21(4):521-5.
Postmenopausal osteoporosis stems from an imbalance in osteoclastic bone resorption with respect to osteoblastic bone formation, a consequence of estrogen deficiency. The nuclear factor-kappaB (NF-kappaB) signal transduction pathway is critical for osteoclast formation and resorption, and suppression of NF-kappaB activation has been shown to block bone resorption in vitro, and to ameliorate inflammatory bone loss in vivo. The use of NF-kappaB antagonists to blunt the bone loss associated with estrogen deficiency however, has not been previously reported. In this study, we investigated whether pharmacological suppression of NF-kappaB signaling protects mice against ovariectomy (ovx)-induced bone loss. Ovx mice were treated with the potent NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) for 4 weeks and bone mineral density (BMD) and indices of bone structure quantitated by dual-energy X-ray absorptiometry (DXA), and micro-computed tomography (microCT). In vivo indices of bone resorption were quantitated in mouse serum using the biochemical marker C-terminal telopeptide of collagen (CTx). Our data revealed that NF-kappaB suppression significantly prevented ovx-induced bone destruction by preventing the increase in ovx-induced osteoclastic bone resorption. Our data suggest that NF-kappaB inhibitors may represent novel anticatabolic therapeutic agents for the amelioration of postmenopausal bone loss.
绝经后骨质疏松症源于破骨细胞骨吸收与成骨细胞骨形成之间的失衡，这是雌激素缺乏的结果。核因子-κB（NF-κB）信号转导通路对破骨细胞的形成和吸收至关重要，并且已表明抑制NF-κB激活可在体外阻断骨吸收，并在体内改善炎症性骨质流失。然而，此前尚未有关于使用NF-κB拮抗剂来减轻与雌激素缺乏相关的骨质流失的报道。在本研究中，我们调查了NF-κB信号的药理抑制是否能保护小鼠免受卵巢切除（ovx）诱导的骨质流失。用强效NF-κB抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）对ovx小鼠进行4周治疗，并用双能X线吸收法（DXA）和微型计算机断层扫描（microCT）对骨密度（BMD）和骨结构指标进行定量分析。使用生化标志物胶原C末端肽（CTx）对小鼠血清中的骨吸收体内指标进行定量分析。我们的数据显示，NF-κB抑制通过阻止ovx诱导的破骨细胞骨吸收增加，显著预防了ovx诱导的骨破坏。我们的数据表明，NF-κB抑制剂可能是用于改善绝经后骨质流失的新型抗分解代谢治疗药物。
