Central IL-1 receptor signaling regulates bone growth and mass
Central IL-1 receptor signaling regulates bone growth and mass
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DOI：
10.1073/pnas.0502562102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Bab, I
中科院分区：
文献类型：
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作者：
Bajayo, A;Goshen, I;Bab, I
促炎细胞因子IL-1通过下丘脑IL-1受体1型(IL-1 RI)发挥作用，激活已知的抑制骨形成的途径，如下丘脑-垂体-肾上腺皮质轴和交感神经系统。此外，外周IL-1被认为是性激素耗竭和肿瘤坏死因子引起的骨丢失的介质。在这里，我们报告了一种意想不到的低骨量(LBM)表型，包括IL-1RI缺陷小鼠(IL-1rKO小鼠)的骨生长障碍。使用小鼠胶质纤维酸性蛋白启动子(IL-1raTG小鼠)将人IL-1受体拮抗剂定向过表达到中枢神经系统，得到了类似的表型，表明中枢IL-1RI沉默是LBM诱导的原因。骨重建分析表明，IL-1rKO和IL-1raTG导致LBM的过程主要表现为破骨细胞数量翻倍。基因修饰不会降低睾酮水平或增加皮质酮血清水平，这表明除了性腺和下丘脑-垂体-肾上腺皮质轴以外的其他系统介导了中枢IL-1RI对骨骼的影响。我们进一步证明，WT小鼠在骨骼中表达小鼠IL-1ra，但在下丘脑中不表达。由于低水平的IL-1存在于两个组织中，提示骨骼组织的IL-1活性通常受到抑制，而中枢IL-1产生对IL-1RI信号的持续生理刺激。尽管中枢IL-1RI信号与骨重建之间的联系尚不清楚，但破骨细胞在缺失的情况下的发生表明，正常情况下，破骨细胞通过抑制骨吸收来控制骨生长和骨质量。
The proinflammatory cytokine IL-1, acting via the hypothalamic IL-1 receptor type 1 (IL-1 RI), activates pathways known to suppress bone formation such as the hypothalamo pituitary-adrenocortical axis and the sympathetic nervous system. In addition, peripheral IL-1 has been implicated as a mediator of the bone loss induced by sex hormone depletion and TNF. Here, we report an unexpected low bone mass (LBM) phenotype, including impairment of bone growth, in IL-1RI-deficient mice (IL-1rKO mice). Targeted overexpression of human IL-1 receptor antagonist to the central nervous system using the murine glial fibrillary acidic protein promoter (IL-1raTG mice) resulted in a similar phenotype, implying that central IL-1RI silencing is the causative process in the LBM induction. Analysis of bone remodeling indicates that the process leading to the LBM in both IL-1rKO and IL-1raTG is characterized mainly by doubling the osteoclast number. Either genetic modification does not decrease testosterone or increase corticosterone serum levels, suggesting that systems other than the gonads and hypothalamo pituitary-adrenocortical axis mediate the central IL-1RI effect on bone. We further demonstrate that WT mice express mouse IL-1ra in bone but not in the hypothalamus. Because low levels of IL-1 are present in both tissues, it is suggested that skeletal IL-1 activity is normally suppressed, whereas central IL-1 produces a constant physiologic stimulation of IL-1 RI signaling. Although the pathway connecting the central IL-1RI signaling to bone remodeling remains unknown, the outburst of osteoclastogenesis in its absence suggests that normally it controls bone growth and mass by tonically restraining bone resorption.