Kimble R B, Matayoshi A B, Vannice J L, Kung V T, Williams C, Pacifici R
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
Endocrinology. 1995 Jul;136(7):3054-61. doi: 10.1210/endo.136.7.7789332.
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.
大量证据支持雌激素通过阻断骨骼或骨髓中细胞因子的产生来预防骨质流失这一假说。然而，诸如白细胞介素-1（IL-1）、IL-6和肿瘤坏死因子（TNF）等候选因子的作用仍存在争议。由于IL-1和TNF在骨骼中具有许多相加和/或协同作用，我们测试了这样一个假说，即同时阻断IL-1和TNF对于预防卵巢切除（ovx）后快速骨质流失的初始阶段是必需的。为此，将大鼠进行卵巢切除，并分别用IL-1受体拮抗剂（IL-1ra，一种IL-1抑制剂）或TNF结合蛋白（TNFbp，一种TNF抑制剂）治疗2周。通过双能X线吸收法测量，ovx增加了骨髓细胞IL-1和TNF的分泌，并降低了股骨远端的骨密度。IL-1ra和TNFbp均可减少ovx诱导的骨质流失，而同时用IL-1ra和TNFbp治疗可完全预防骨质流失。IL-1ra和TNFbp联合治疗可降低尿吡啶啉交联水平，这是一种反映破骨细胞数量和破骨细胞活性的骨吸收标志物，而单独使用任何一种抑制剂的效果较差。IL-1ra和TNFbp均可减少骨内膜表面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相加作用，这表明抑制破骨细胞生成和刺激骨形成并不能解释IL-1ra和TNFbp相加的保骨作用。这些抑制剂对假手术大鼠没有影响，表明它们特异性地阻断了雌激素依赖性事件。总之，这些数据表明，在ovx后的早期阶段，IL-1和TNF在诱导骨质流失中起关键的因果作用，其作用机制是刺激骨吸收和抑制骨形成。
