The ubiquitination and deubiquitination enzymes ensure the stability and proper function of most cellular proteins. Disturbance of either enzyme compromises tissue homeostasis. We recently have identified that the ubiquitin‐specific protease 34 (USP34) contributes to bone formation by promoting osteogenic differentiation of mesenchymal stem cells. However, its role in bone resorption, which couples bone formation, remains unknown. Here we show that knockdown of Usp34 promotes osteoclast differentiation of RAW264.7 cells. Conditional knockout of Usp34 in bone marrow–derived macrophages (BMMs) or in osteoclasts leads to elevated osteoclast function and low bone mass. Mechanically, we identify that USP34 restrains NF‐κB signaling by deubiquitinating and stabilizing the NF‐κB inhibitor alpha (IκBα). Overexpression of IκBα represses osteoclastic hyperfunction of Usp34‐deficient RAW264.7 cells. Collectively, our results show that USP34 inhibits osteoclastogenesis by regulating NF‐κB signaling. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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泛素特异性蛋白酶 34 通过调节 NF-κB 信号传导抑制破骨细胞分化。

泛素化和去泛素化酶确保大多数细胞蛋白质的稳定性和正常功能。任何一种酶的紊乱都会损害组织稳态。我们最近发现，泛素特异性蛋白酶 34 (USP34) 通过促进间充质干细胞的成骨分化促进骨形成。然而，它在结合骨形成的骨吸收中的作用仍然未知。在这里，我们显示Usp34的敲低促进 RAW264.7 细胞的破骨细胞分化。Usp34的条件淘汰赛在骨髓来源的巨噬细胞 (BMM) 或破骨细胞中会导致破骨细胞功能升高和骨量减少。机械地，我们发现 USP34 通过去泛素化和稳定 NF-κB 抑制剂 α (IκBα) 来抑制 NF-κB 信号传导。IκBα的过表达抑制Usp34 缺陷型RAW264.7 细胞的破骨细胞功能亢进。总的来说，我们的结果表明 USP34 通过调节 NF-κB 信号传导来抑制破骨细胞生成。© 2020 美国骨与矿物研究学会。