Suppression of NF-κB Increases Bone Formation and Ameliorates Osteopenia in Ovariectomized Mice
Suppression of NF-κB Increases Bone Formation and Ameliorates Osteopenia in Ovariectomized Mice
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DOI：
10.1210/en.2010-0399
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Ohya, Keiichi
中科院分区：
文献类型：
--
作者：
Alles, Neil;Soysa, Niroshani S.;Ohya, Keiichi
骨退行性疾病，包括骨质疏松症，破坏破骨细胞骨吸收和成骨细胞骨形成之间的良好平衡。合成代谢和抗分解代谢作用的单药疗法作为改善此类病症的药物靶点是有吸引力的。抑制核因子（NF）-κ B可降低破骨细胞的骨吸收。然而，NF-κ B B抑制剂对成骨细胞和骨形成的作用是最小的，并且没有得到很好的研究。使用一种名为S1627的NF-κ B抑制剂，我们证明了NF-κ B的抑制通过上调成骨细胞特异性基因如I型胶原、碱性磷酸酶和骨桥蛋白的mRNA来增加体外成骨细胞分化和骨形成。此外，S1627能够增加小鼠颅骨缺损模型中的骨形成和修复骨缺损。为了确定NF-κ B对骨质疏松模型的影响，我们在假手术或卵巢切除的12周龄小鼠中每天两次注射两种剂量的抑制剂（25和50 mg/kg.d），并在4周后将其处死。通过微焦点计算机断层扫描和组织形态计量学测定S1627对骨小梁的合成代谢作用。与假手术小鼠相比，卵巢切除动物的骨密度显著增加。成骨细胞相关指标如成骨细胞表面、矿物质沉积率和骨形成率在S1627处理的动物中以剂量依赖性方式增加。S1627抑制NF-κ B可增加卵巢切除小鼠的骨小梁体积。S1627还能抑制破骨细胞的数量，抑制破骨细胞表面与骨表面的接触。NF-κ B抑制剂S1627剂量依赖性地降低体外破骨细胞生成和骨吸收活性。总的来说，我们的研究结果表明，NF-κ B抑制剂是有效的治疗骨相关疾病，由于其双重合成代谢和抗吸收活性。（内分泌学151：4626-4634，2010）
Bone degenerative diseases, including osteoporosis, impair the fine balance between osteoclast bone resorption and osteoblast bone formation. Single-agent therapy for anabolic and anticatabolic effects is attractive as a drug target to ameliorate such conditions. Inhibition of nuclear factor (NF)-kappa B reduces the osteoclast bone resorption. The role of NF-kappa B inhibitors on osteoblasts and bone formation, however, is minimal and not well investigated. Using an established NF-kappa B inhibitor named S1627, we demonstrated that inhibition of NF-kappa B increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model. To determine the effect of NF-kappa B on a model of osteoporosis, we injected two doses of inhibitor (25 and 50 mg/kg.d) twice a day in sham-operated or ovariectomized 12-wk-old mice and killed them after 4 wk. The anabolic effect of S1627 on trabecular bone was determined by micro focal computed tomography and histomorphometry. Bone mineral density of inhibitor-treated ovariectomized animals was significantly increased compared with sham-operated mice. Osteoblast-related indices like osteoblast surface, mineral apposition rate, and bone formation rate were increased in S1627-treated animals in a dose-dependent manner. NF-kappa B inhibition by S1627 increased the trabecular bone volume in ovariectomized mice. Furthermore, S1627 could inhibit the osteoclast number, and osteoclast surface to bone surface. In vitro osteoclastogenesis and bone resorbing activity were dose-dependently reduced by NF-kappa B inhibitor S1627. Taken collectively, our results suggest that NF-kappa B inhibitors are effective in treating bone-related diseases due to their dual anabolic and antiresorptive activities. (Endocrinology 151: 4626-4634, 2010)