St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia.
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Bone. 2018 Jul;112:120-127. doi: 10.1016/j.bone.2018.04.015. Epub 2018 Apr 19.
Bone loss associated with estrogen deficiency occurs due to a high level of bone remodelling, with a greater increase in the level of osteoclast-mediated bone resorption than osteoblast-mediated bone formation. Early studies showed that Interleukin-6 (IL-6) inhibition could prevent the increase in osteoclast numbers associated with ovariectomy. However, IL-6 signals through two possible pathways: classic IL-6 signalling (cis) utilizes a membrane-bound IL-6 receptor (IL-6R), while IL-6 trans-signalling occurs through a soluble IL-6R (sIL-6R). It is not known which of these pathways mediates the bone loss after ovariectomy. We therefore sought to determine whether specific pharmacological inhibition of IL-6 trans-signalling could prevent ovariectomy-induced bone loss in mice. We report that IL-6 trans-signalling inhibition prevented the increase in osteoclasts, and trabecular bone loss, associated with ovariectomy. IL-6 trans-signalling inhibition also reduced bone formation rate, but did not prevent the increase in osteoblast numbers. In contrast, cortical bone loss was not prevented by any IL-6 signalling inhibitor. This suggests that local production of sIL-6R mediates trabecular bone loss in estrogen deficiency, but the increased cortical bone resorption that leads to marrow expansion is independent of IL-6 signalling.
与雌激素缺乏相关的骨丢失是由于高水平的骨重塑引起的，破骨细胞介导的骨吸收水平比成骨细胞介导的骨形成水平增加得更大。早期研究表明，白细胞介素-6 (IL-6) 抑制可以防止与卵巢切除相关的破骨细胞数量增加。然而，IL-6 通过两种可能的途径传递信号：经典的 IL-6 信号通路（顺式）利用膜结合的 IL-6 受体 (IL-6R)，而 IL-6 转信号通路通过可溶性 IL-6R (sIL-6R) 发生。目前尚不清楚这些途径中的哪一种介导了卵巢切除术后的骨丢失。因此，我们试图确定特异性抑制 IL-6 转信号是否可以防止卵巢切除引起的小鼠骨丢失。我们报告说，IL-6 转信号通路抑制可防止与卵巢切除相关的破骨细胞增加和小梁骨丢失。IL-6 转信号通路抑制还降低了骨形成率，但不能防止成骨细胞数量的增加。相比之下，任何 IL-6 信号抑制剂都不能预防皮质骨丢失。这表明局部产生的 sIL-6R 介导了雌激素缺乏症中的小梁骨丢失，但导致骨髓扩张的增加的皮质骨吸收与 IL-6 信号无关。
