The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone
The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone
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DOI：
10.1074/jbc.m112.393363
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发表时间：
2013-03-08
影响因子：
4.8
通讯作者：
McCauley, Laurie K.
中科院分区：
文献类型：
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作者：
Cho, Sun Wook;Pirih, Flavia Q.;McCauley, Laurie K.
甲状旁腺激素和IL-6信号在造血和骨骼生物学中都发挥着关键作用，但它们之间的相互依赖关系尚不清楚。本研究旨在探讨IL-6和可溶性IL-6受体(sIL-6R)对甲状旁腺激素(PTH)造血和骨骼功能的影响。在骨微环境中，甲状旁腺素刺激体外原代成骨细胞培养和体内IL-6(+/+)和IL-6(-/-)小鼠骨髓中sIL-6R蛋白水平。与IL-6(+/+)相比，IL-6(-/-)骨髓中PTH介导的造血细胞扩增作用减弱，而sIL-6R在IL-6(-/-)骨髓培养中较IL-6(+/+)骨髓培养更早增强PTH作用。用sgp130(可溶性糖蛋白130受体)阻断sIL-6R信号可抑制IL-6(-/-)骨髓中甲状旁腺素依赖的造血细胞的扩增。在骨骼系统中，尽管间歇性给予IL-6(+/+)和IL-6(-/-)小鼠的甲状旁腺素可导致相似的合成代谢作用，但阻断sIL-6R可显著减弱甲状旁腺素的合成代谢作用。SIL-6R在体外对成骨细胞的增殖或分化无直接影响，但在骨髓微环境中可上调髓系细胞的增殖和骨髓间充质干细胞募集剂转化生长因子-β1的产生。总的来说，sIL-6R显示了孤儿功能，并介导了骨骼中的甲状旁腺素合成代谢作用，并与造血系统中髓系细胞的支持有关。
Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6 (+/+) and IL-6 (-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-beta 1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.