Role of Inducible Nitric Oxide Synthase in Skeletal Adaptation to Acute Increases in Mechanical Loading
作者:Makoto Watanuki、Akinori Sakai、Takeshi Sakata、Hiroshi Tsurukami、Masao Miwa、Yasuo Uchida、Ken Watanabe、Kyoji Ikeda、Toshitaka Nakamura
DOI:10.1359/jbmr.2002.17.6.1015
日期:——
To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail‐suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/− mice responded to subsequent 14‐day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS−/− mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS−/− mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS−/− mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.
为了明确一氧化氮(NO)在骨骼负荷下调节骨代谢中的作用,我们在尾悬吊模型中研究了诱导型一氧化氮合酶(iNOS)基因敲除小鼠。胫骨近端组织形态学分析表明,在所有 iNOS 基因型小鼠中,尾悬吊 7 天会降低骨量(BV/TV)和骨形成率(BFR/BS),增加破骨细胞表面(Oc.S/BS)。iNOS+/+ 和 iNOS+/- 小鼠对随后 14 天的再加载均有反应,BV/TV 和 BFR/BS 增加,Oc.S/BS 减少,而 iNOS-/- 小鼠的这些反应消失。尾部悬浮后扁平的成骨细胞在随后的重装过程中出现了立方体。通过免疫组化在这些成骨细胞和骨细胞中检测到了 iNOS 的免疫反应。用氮氧化物供体硝酸甘油(NG)处理 iNOS-/- 小鼠后,重装后的这些缺陷反应得到了挽救。相反,用 NOS 抑制剂氨基胍(AG)处理 iNOS+/+ 小鼠,则可抑制其反应。在骨髓细胞培养中,iNOS-/-小鼠重负荷后产生的矿化结节明显减少。综上所述,我们的研究结果表明,iNOS 在成骨细胞中产生的 NO 对调整骨转换和增加成骨活性起着关键作用,以应对尾悬吊后机械负荷的急性增加。