Forwood M R
Department of Anatomical Sciences, The University of Queensland, Brisbane, Australia.
J Bone Miner Res. 1996 Nov;11(11):1688-93. doi: 10.1002/jbmr.5650111112.
In vivo, indomethacin blockade of bone formation has been used to illustrate the role of prostaglandins. Indomethacin blocks the constitutive (COX-1) and inducible (COX-2) forms of cyclo-oxygenase, and is therefore nonspecific in its action. To test the hypothesis that COX-2 mediates the bone formation response to loading, rats were treated with vehicle, NS-398 (a specific COX-2 inhibitor) or indomethacin at 0.02, 0.2, or 2.0 mg/kg p.o. 3 h before loading the right tibia in four-point bending. Bending or sham loads of 65 N were applied for one bout of 300 cycles and bone formation assessed 5-8 days after loading. Mechanically induced bone formation at the endocortical surface was calculated by subtracting formation indices of the left leg (control) from those of the right (loaded), and woven bone surface and area were measured at the periosteal surface. Endocortical bone formation was significantly increased by bending but not sham loading (p < 0.05). The increase in the endocortical bone formation rate and mineralizing surface caused by bending was only partially inhibited by indomethacin, even at the highest dose, whereas NS-398 completely blocked bone formation at all doses (p < 0.05). The mineral apposition rate was depressed in a dose-response fashion by NS-398 (p < 0.05), but not by indomethacin. Woven bone formation at the periosteal surface was not prevented by treatment with indomethacin nor NS-398, suggesting that its formation is not dependent on prostaglandin production. These data suggest that induction of COX-2 is important for lamellar bone formation elicited by mechanical strain.
在体内，吲哚美辛对骨形成的阻断作用已被用于阐明前列腺素的作用。吲哚美辛可阻断环氧化酶的组成型（COX - 1）和诱导型（COX - 2）形式，因此其作用是非特异性的。为了验证COX - 2介导对负荷的骨形成反应这一假说，在对大鼠右胫骨进行四点弯曲负荷前3小时，分别用赋形剂、NS - 398（一种特异性COX - 2抑制剂）或0.02、0.2或2.0 mg/kg口服剂量的吲哚美辛对大鼠进行处理。施加65 N的弯曲或假负荷，持续300个周期，负荷后5 - 8天评估骨形成情况。通过用右腿（负荷侧）的形成指数减去左腿（对照侧）的形成指数来计算机械诱导的内皮质表面骨形成，并测量骨膜表面的编织骨表面和面积。弯曲可显著增加内皮质骨形成，但假负荷则无此作用（p < 0.05）。即使在最高剂量下，吲哚美辛也只能部分抑制弯曲引起的内皮质骨形成率和矿化表面的增加，而NS - 398在所有剂量下均完全阻断骨形成（p < 0.05）。NS - 398以剂量反应方式降低矿化沉积率（p < 0.05），但吲哚美辛无此作用。吲哚美辛和NS - 398处理均不能阻止骨膜表面编织骨的形成，提示其形成不依赖于前列腺素的产生。这些数据表明，COX - 2的诱导对于机械应变引起的板层骨形成很重要。
