IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation
IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation
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DOI：
10.1172/jci30074
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发表时间：
2007-01-01
影响因子：
15.9
通讯作者：
Pacifici, Roberto
中科院分区：
文献类型：
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作者：
Gao, Yuhao;Grassi, Francesco;Pacifici, Roberto
T细胞产生的细胞因子在炎症、感染和雌激素缺乏引起的骨质流失中起着关键作用。ifn - γ是激活T辅助细胞的主要产物，可以作为促或抗吸收细胞因子发挥作用，但ifn - γ在骨中具有可变作用的原因尚不清楚。本研究表明，ifn - γ通过直接靶向破骨细胞前体来抑制破骨细胞的形成，但通过刺激抗原依赖性T细胞活化和T细胞分泌破骨因子RANKL和tnf - α来间接刺激破骨细胞的形成和促进骨吸收。对ifn - γ在3种骨质流失小鼠模型（卵巢切除、LPS注射和通过沉默T细胞中tgf - β信号引起的炎症）中的体内效应的分析表明，ifn - γ在这些情况下的净效应是刺激骨吸收和骨质流失。综上所述，ifn - γ在体内具有直接抗破骨和间接促破骨的特性。在雌激素缺乏、感染和炎症的情况下，这两种相反力量的净平衡偏向于骨吸收。因此，抑制ifn - γ信号可能是一种同时减少常见骨质疏松症炎症和骨质流失的新策略。
T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. in summary, IFN-gamma has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.