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Cytokine-induced nitric oxide inhibits bone resorption by inducing apoptosis of osteoclast progenitors and suppressing osteoclast activity

机译:细胞因子诱导的一氧化氮通过诱导破骨细胞祖细胞凋亡和抑制破骨细胞活性来抑制骨吸收

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摘要

Interferon-gamma (IFN-gamma) has been shown to inhibit interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) stimulated bone resorption by strongly stimulating nitric oxide (NO) synthesis. Here we studied the mechanisms underlying this inhibition. Osteoclasts were generated in 10-day cocultures of mouse osteoblasts and bone marrow cells and the effect of cytokine-induced NO on osteoclast formation and activity was determined. Stimulation of the cocultures with IL-1 beta, TNF-alpha and IFN-gamma markedly enhanced NO production by 50- to 70-fold, and this was found to be derived predominantly from the osteoblast cell layer. When high levels of NO were induced by cytokines during early stages of the cocultures, osteoclast formation was virtually abolished and bone resorption markedly inhibited. Cytokine stimulation during the latter stages of coculture also resulted in inhibition of bone resorption, but here the effects were mainly due to an inhibitory effect on osteoclast activity. At all stages, however, the inhibitory effects of cytokines on osteoclast formation and activity were blocked by the NO-synthase inhibitor L-NMMA. Further investigations suggested that the NO-mediated inhibition of osteoclast formation was due in part to apoptosis of osteoclast progenitors. Cytokine stimulation during the early stage of the culture caused a large increase in apoptosis of bone marrow cells, and these effects were blocked by L-NMMA and enhanced by NO donors. We found no evidence of apoptosis in osteoclasts exposed to high levels of cytokine-induced NO at any stage in the culture, however, or of apoptosis affecting mature osteoclasts exposed to high levels of NO, suggesting that immature cells in the bone marrow compartment are most sensitive to NO-induced apoptosis. In summary, these studies identify NO as a potentially important osteoblast-osteoclast coupling factor which has potent inhibitory effects on bone resorption. These actions, in turn, are mediated by inhibition of osteoclast formation probably due to NO-induced apoptosis of osteoclast progenitors and by inhibition of the resorptive activity of mature osteoclasts.
机译:干扰素-γ(IFN-γ)已显示通过强烈刺激一氧化氮(NO)的合成抑制白介素1(IL-1)和肿瘤坏死因子α(TNF-α)刺激的骨吸收。在这里,我们研究了这种抑制的机制。在小鼠成骨细胞和骨髓细胞共培养10天后产生破骨细胞,并测定了细胞因子诱导的NO对破骨细胞形成和活性的影响。用IL-1β,TNF-α和IFN-γ对共培养物的刺激显着提高了NO的产生50到70倍,并且发现这主要来自成骨细胞层。当在共培养的早期阶段由细胞因子诱导高水平的NO时,破骨细胞的形成实际上被消除,并且骨吸收被明显抑制。在共培养的后期,细胞因子的刺激也导致骨吸收的抑制,但是这里的作用主要是由于对破骨细胞活性的抑制作用。然而,在所有阶段,细胞因子对破骨细胞形成和活性的抑制作用均被NO合酶抑制剂L-NMMA阻断。进一步的研究表明,NO介导的破骨细胞形成抑制部分归因于破骨细胞祖细胞的凋亡。培养初期的细胞因子刺激引起骨髓细胞凋亡的大量增加,这些作用被L-NMMA阻断并被NO供体所增强。我们在培养的任何阶段均未发现暴露于高水平细胞因子诱导的NO的破骨细胞凋亡的证据,也未发现暴露于高水平NO的成熟破骨细胞的凋亡影响的细胞凋亡的证据,这表明骨髓腔中未成熟的细胞最多。对NO诱导的细胞凋亡敏感。总之,这些研究将NO鉴定为潜在的重要成骨细胞-破骨细胞偶联因子,对骨吸收具有有效的抑制作用。反过来,这些作用是由破骨细胞形成的抑制介导的,这可能是由于NO诱导的破骨细胞祖细胞的凋亡以及对成熟破骨细胞的吸收活性的抑制。

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