Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions
Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions
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DOI：
10.1007/s00774-017-0890-z
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发表时间：
2018-11-01
影响因子：
3.3
通讯作者：
Miyamoto, Takeshi
中科院分区：
文献类型：
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作者：
Oya, Akihito;Katsuyama, Eri;Miyamoto, Takeshi
破骨细胞和异物巨细胞（FBGCs）来自共同的祖细胞和共享的属性，如多核能力诱导细胞-细胞融合;然而，这些细胞之间的谱系决定的机制仍然不清楚。在这里，我们表明，在炎症条件下，破骨细胞被刺激的方式类似于M1巨噬细胞，而形成的FBGC，表现出M2样表型，被抑制的方式类似于M1/M2巨噬细胞极化。肿瘤坏死因子受体相关因子6（Traf 6）的条件性敲除在体内和体外抑制FBGC/破骨细胞极化。Traf 6基因缺失的小鼠在出生后不久就死亡，但我们发现成年人的Traf 6基因缺失并没有导致死亡，而是抑制了破骨细胞的激活，并阻止了炎症条件下的FBGC抑制。因此，在体内和体外，Traf 6缺失显著抑制了基底破骨细胞生成，并伴有骨量增加。脂多糖诱导的破骨细胞形成和骨溶解在Traf 6条件性基因敲除小鼠中被显著抑制。我们的研究结果表明，Traf 6在调节M1破骨细胞和M2 FBGC极化中起着至关重要的作用，并且是阻断FBGC抑制、拮抗炎症条件下的骨溶解和增加成人骨量而无不良反应的潜在治疗靶点。
Osteoclasts and foreign body giant cells (FBGCs) are derived from common progenitors and share properties such as multi-nucleation capacity induced by cell-cell fusion; however, mechanisms underlying lineage determination between these cells remain unclear. Here we show that, under inflammatory conditions, osteoclasts are stimulated in a manner similar to M1 macrophages, while formation of FBGCs, which exhibit M2-like phenotypes, is inhibited in a manner similar to that seen in M1/M2 macrophage polarization. FBGC/osteoclast polarization was inhibited by conditional knockout of tumor necrosis factor receptor associated factor 6 (Traf6) in adults in vivo and in vitro. Traf6-null mice were previously reported to die soon after birth, but we found that Traf6 deletion in adults did not cause lethality but rather inhibited osteoclast activation and prevented FBGC inhibition under inflammatory conditions. Accordingly, basal osteoclastogenesis was significantly inhibited by Traf6 deletion in vivo and in vitro and accompanied by increased bone mass. Lipopolysaccharide-induced osteoclast formation and osteolysis were significantly inhibited in Traf6 conditional knockout mice. Our results suggest that Traf6 plays a crucial role in regulating M1 osteoclast and M2 FBGC polarization and is a potential therapeutic target in blocking FBGC inhibition, antagonizing osteolysis in inflammatory conditions, and increasing bone mass without adverse effects in adults.