Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period.
Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period.
复制标题
DOI：
10.1210/endo.136.7.7789332
复制
发表时间：
1995-07
期刊：
影响因子：
4.8
通讯作者：
R. Kimble;A. Matayoshi;J. Vannice;V. Kung;C. Williams;R. Pacifici
中科院分区：
文献类型：
--
作者：
R. Kimble;A. Matayoshi;J. Vannice;V. Kung;C. Williams;R. Pacifici
大量证据支持雌激素通过阻断骨或骨髓中细胞因子的产生来防止骨丢失的假设。然而，对候选因子如白细胞介素-1（IL-1）、IL-6和肿瘤坏死因子（TNF）的作用仍存在争议。由于IL-1和TNF在骨中具有许多相加和/或协同作用，因此我们检验了以下假设：需要同时阻断IL-1和TNF以防止卵巢切除术（OVX）后快速骨丢失的初始阶段。为此，切除大鼠卵巢，并用IL-1受体拮抗剂（IL-1 ra）（IL-1的抑制剂）或TNF结合蛋白（TNF bp）（TNF的抑制剂）治疗2周。双能X线骨密度测定法显示，卵巢切除可增加骨髓细胞分泌IL-1和TNF，降低股骨远端骨密度。IL-1 ra和TNFbp均能降低卵巢诱导的骨丢失，同时用IL-1 ra和TNFbp治疗可完全预防卵巢诱导的骨丢失。联合治疗IL-1 ra和TNFbp减少尿吡啶啉交联，反映破骨细胞数量和破骨细胞活性的骨吸收的标志物，而单独使用任一抑制剂的治疗效果较差。IL-1 ra和TNFbp都减少了皮质内表面上破骨细胞的数量并刺激骨形成，但这两种抑制剂对这些指标没有累加效应，这表明抑制破骨细胞生成和刺激骨形成并不能解释IL-1 ra和TNFbp的累加骨保留效应。这些抑制剂在假手术大鼠中没有效果，表明它们特异性阻断了雌激素依赖性事件。总之，这些数据表明，在OVX后早期，IL-1和TNF在诱导骨丢失中起关键的因果作用，并通过刺激骨吸收和抑制骨形成来实现。
Considerable evidence supports the hypothesis that estrogen prevents bone loss by blocking the production of cytokines in bone or bone marrow. However, controversy remains on the role of candidate factors, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). As IL-1 and TNF have many additive and/or synergistic effects in bone, we tested the hypothesis that the simultaneous block of IL-1 and TNF is required to prevent the initial phase of rapid bone loss that follows ovariectomy (ovx). To this aim, rats were ovariectomized and treated for 2 weeks with either IL-1 receptor antagonist (IL-1ra), an inhibitor of IL-1, or TNF-binding protein (TNFbp), an inhibitor of TNF. Ovx increased bone marrow cell secretion of IL-1 and TNF and decreased the bone density of the distal femur, as measured by dual energy x-ray absorptiometry. Ovx-induced bone loss was decreased by both IL-1ra and TNFbp and completely prevented by simultaneous treatment with IL-1ra and TNFbp. Combined treatment with IL-1ra and TNFbp decreased urinary pyridinoline cross-links, a marker of bone resorption that reflects osteoclast number and osteoclast activity, whereas treatment with either inhibitor alone was less effective. Both IL-1ra and TNFbp decreased the number of osteoclasts on the endocortical surfaces and stimulated bone formation, but the two inhibitors had no additive effects on these indexes, suggesting that inhibition of osteoclastogenesis and stimulation of bone formation do not account for the additive bone-sparing effects of IL-1ra and TNFbp. These inhibitors had no effect in sham-operated rats, indicating that they specifically blocked estrogen-dependent events. In conclusion, these data indicate that in the early post-ovx period, IL-1 and TNF play a critical causal role in inducing bone loss and do so by stimulating bone resorption and inhibiting bone formation.