Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone
Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone
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DOI：
10.1016/j.bone.2015.08.005
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发表时间：
2015-12-01
期刊：
影响因子：
4.1
通讯作者：
Sims, Natalie A.
中科院分区：
文献类型：
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作者：
Johnson, Rachelle W.;McGregor, Narelle E.;Sims, Natalie A.
白细胞介素-6（IL-6）和白细胞介素-11（IL-11）受体（分别为IL-6 R和IL-11 R）均在破骨细胞中表达，并通过糖蛋白130（gp 130）辅助受体发出信号，但该途径的生理作用尚不清楚。为了确定gp 130信号在破骨细胞中的关键作用，我们使用组织蛋白酶K Cre（CtskCre）来破坏破骨细胞中的gp 130信号。来自CtskCre.gp130（f/f）小鼠的骨髓巨噬细胞在体外比来自CtskCre.gp130（w/w）小鼠的细胞产生更多的破骨细胞;这些破骨细胞也比对照组更大，具有更多的细胞核。虽然在体内没有观察到破骨细胞数量的增加，但CtskCre.gp130（f/f）小鼠松质骨表面上的破骨细胞比对照小鼠更分散，但没有通过血清CTX 1水平或松质骨软骨残留物检测到的功能缺陷。然而，与对照组相比，雄性CtskCre.gp130（f/f）小鼠的骨小梁成骨细胞数量和矿化表面显著降低，这与12周龄时骨小梁体积显著降低相关。此外，CtskCre.gp130（f/f）小鼠在这个年龄表现出极大的骨膜骨形成抑制，表明双标记表面和矿物质沉积率的显着降低。到26周龄时，CtskCre.gp130（f/f）小鼠表现出比CtskCre.gp130（w/w）对照组更窄的股骨，具有更低的骨膜和皮质内周长。由于IL-6和IL-11 R全基因敲除小鼠表现出相似的股骨宽度减少，我们还评估了这些品系中的骨膜骨形成，发现雄性IL-6敲除小鼠中的骨形成表面也减少。这些数据表明，破骨细胞中的IL-6/gp 130信号传导对于体内正常的骨吸收不是必需的，但是通过分别刺激破骨细胞衍生的“偶联因子”和“骨传递素”来促进成骨细胞活性，从而维持雄性小鼠的小梁和骨膜骨形成。(C)2015 Elsevier Inc. All rights reserved.
Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively. (C) 2015 Elsevier Inc. All rights reserved.