Ralston S H, Ho L P, Helfrich M H, Grabowski P S, Johnston P W, Benjamin N
Department of Medicine & Therapeutics, University of Aberdeen Medical School, Foresterhill, U.K.
J Bone Miner Res. 1995 Jul;10(7):1040-9. doi: 10.1002/jbmr.5650100708.
Nitric oxide (NO) has been reported to inhibit osteoclastic bone resorption, yet potent stimulators of bone resorption, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are known to stimulate NO production. This paradox prompted us to reinvestigate the relationship between NO production and bone resorption in mouse calvarial organ cultures. Control cultures and those stimulated with calciotropic hormones and individual cytokines produced little NO, and under these conditions the NO synthase inhibitor, L-NG-monomethyl arginine (LMMA), had no significant effect on bone resorption. Cytokine combinations were much more potent stimulators of NO production than individual cytokines. Dramatic stimulation of NO production and inhibition of bone resorption resulted when gamma-interferon (IFN) was combined with IL-1 or TNF and these effects were reversed by LMMA. IFN had no effect on bone resorption and little effect on NO production when used alone or in combination with calciotropic hormones, however, suggesting that IFN selectively inhibits cytokine-induced bone resorption by generating large amounts of NO. IL-1 and TNF acted together to stimulate NO production but to a lesser degree than when combined with IFN. LMMA inhibited bone resorption induced by IL-1 and TNF, suggesting that lower concentrations of NO stimulate bone resorption. Experiments with the pharmacological NO donor S-nitroso-acetyl-penicillamine (SNAP) supported this view in showing generalized suppression of bone resorption at high SNAP concentrations, but potentiation of IL-1 induced bone resorption at lower SNAP concentrations. We conclude that cytokines are potent inducers of NO in bone and that cytokine-induced NO production has biphasic effects on bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)
据报道，一氧化氮（NO）可抑制破骨细胞介导的骨吸收，然而，已知骨吸收的强效刺激因子，如白细胞介素-1（IL-1）和肿瘤坏死因子（TNF），可刺激NO生成。这一矛盾促使我们重新研究小鼠颅骨器官培养中NO生成与骨吸收之间的关系。对照培养物以及用促钙激素和单个细胞因子刺激的培养物产生的NO很少，在这些条件下，NO合酶抑制剂L-NG-单甲基精氨酸（LMMA）对骨吸收没有显著影响。细胞因子组合比单个细胞因子更能有效刺激NO生成。当γ-干扰素（IFN）与IL-1或TNF联合使用时，会显著刺激NO生成并抑制骨吸收，而这些作用可被LMMA逆转。然而，IFN单独使用或与促钙激素联合使用时，对骨吸收没有影响，对NO生成的影响也很小，这表明IFN通过产生大量NO选择性抑制细胞因子诱导的骨吸收。IL-1和TNF共同作用刺激NO生成，但程度低于与IFN联合使用时。LMMA抑制IL-1和TNF诱导的骨吸收，表明较低浓度的NO刺激骨吸收。使用药理学NO供体S-亚硝基乙酰青霉胺（SNAP）进行的实验支持了这一观点，即高SNAP浓度下骨吸收普遍受到抑制，但低SNAP浓度下IL-1诱导的骨吸收增强。我们得出结论，细胞因子是骨中NO的强效诱导剂，细胞因子诱导的NO生成对骨吸收具有双相作用。（摘要截短于250字）
