NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism
NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism
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DOI：
10.1172/jci38716
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Boyce, Brendan F.
中科院分区：
文献类型：
--
作者：
Yao, Zhenqiang;Xing, Lianping;Boyce, Brendan F.
TNF和RANKL介导常见骨疾病中的骨破坏，包括骨关节炎和RA。它们直接激活破骨细胞前体（OCP）中的NF-κ B典型信号传导以诱导体外破骨细胞形成。然而，与RANKL不同，TNF不能有效激活替代NF-κ B途径以将I κ B蛋白NF-κ B p100加工成NF-κ B p52，在不存在RANKL的情况下，TNF似乎也不能诱导体内破骨细胞形成。在这里，我们表明，TNF限制RANKL和TNF诱导的破骨细胞的形成在体外和体内增加NF-κ B p100蛋白的积累在OCP。相比之下，当小鼠也缺乏NF-κ B p100时，TNF在缺乏RANKL或RANK的小鼠体内诱导了强大的破骨细胞形成，并且缺乏NF-κ B p100的TNF-Tg小鼠比TNF-Tg同窝小鼠具有更严重的关节侵蚀和炎症。TNF（而非RANKL）增加了OCP中TNF受体相关因子3（TRAF 3）的表达，TRAF 3是一种调节B细胞中NF-κ B p100水平的衔接蛋白。TRAF 3 siRNA阻止TNF诱导的NF-κ B p100积聚和破骨细胞生成的抑制。这些发现表明，上调OCP中TRAF 3或NF-κ B p100的表达或抑制NF-κ B P100的降解可以限制常见骨疾病中的骨破坏和炎症诱导的骨丢失。
TNF and RANKL mediate bone destruction in common bone diseases, including osteoarthritis and RA. They activate NF-kappa B canonical signaling directly in osteoclast precursors (OCPs) to induce osteoclast formation in vitro. However, unlike RANKL, TNF does not activate the alternative NF-kappa B pathway efficiently to process the I kappa B protein NF-kappa B p100 to NF-kappa B p52, nor does it appear to induce osteoclast formation in vivo in the absence of RANKL. Here, we show that TNF limits RANKL- and TNF-induced osteoclast formation in vitro and in vivo by increasing NF-kappa B p100 protein accumulation in OCPs. In contrast, TNF induced robust osteoclast formation in vivo in mice lacking RANKL or RANK when the mice also lacked NF-kappa B p100, and TNF-Tg mice lacking NF-kappa B p100 had more severe joint erosion and inflammation than did TNF-Tg littermates. TNF, but not RANKL, increased OCP expression of TNF receptor-associated factor 3 (TRAF3), an adapter protein that regulates NF-kappa B p100 levels in B cells. TRAF3 siRNA prevented TNF-induced NF-kappa B p100 accumulation and inhibition of osteoclastogenesis. These findings suggest that upregulation of TRAF3 or NF-kappa B p100 expression or inhibition of NF-kappa B P100 degradation in OCPs could limit bone destruction and inflammation-induced bone loss in common bone diseases.