TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2
TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2
复制标题
TRAF4通过作为E3泛素连接酶降解Smurf2来正向调节间充质干细胞的成骨分化
DOI：
10.1038/s41418-019-0328-3
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发表时间：
2019-12-01
影响因子：
12.4
通讯作者：
Shen, Huiyong
中科院分区：
文献类型：
--
作者：
Li, Jinteng;Wang, Peng;Shen, Huiyong
肿瘤坏死因子受体相关因子4（TRAF 4）是TRAF家族的成员，在胚胎发生和骨系统发育中起重要作用。骨髓间充质干细胞（MSCs）是体内成骨细胞的主要来源，是骨发育的关键细胞，然而TRAF4是否调控MSCs的成骨能力还未被研究。在这项研究中，我们证明了TRAF4在体外和体内都积极调节MSC的成骨过程。此外，我们进一步证明了TRAF4通过作为E3泛素连接酶介导K48连接的Smurf2在K119位点的泛素化并引起降解来调节MSC的成骨过程。此外，TRAF4在卵巢切除大鼠和骨质疏松症患者的骨切片中异常减少。综上所述，我们的研究结果表明，TRAF4积极调节骨髓间充质干细胞的成骨分化作为E3泛素连接酶降解Smurf2。这些结果强调了TRAF4在骨形成中的关键作用，不仅可以提高MSCs在组织工程中的临床应用，而且可以阐明骨代谢紊乱的发病机制。
TNF receptor-associated factor 4 (TRAF4), a member of the TRAF family, plays an important role in the embryogenesis and development of the bone system. Mesenchymal stem cells (MSCs), which are the primary origin of osteoblasts in vivo, are key cells in bone development; however, whether TRAF4 modulates the osteogenic capacity of MSCs has never been explored. In this study, we demonstrated that TRAF4 positively regulates the osteogenic process of MSCs both in vitro and in vivo. In addition, we further demonstrated that TRAF4 modulates the osteogenic process of MSCs by acting as an E3 ubiquitin ligase to mediate the K48-linked ubiquitination of Smurf2 at the K119 site and cause degradation. Furthermore, TRAF4 was abnormally decreased in bone sections of ovariectomized rat and osteoporosis patients. Taken together, our findings suggest that TRAF4 positively regulates the osteogenic differentiation of MSCs by acting as an E3 ubiquitin ligase to degrade Smurf2. These results emphasize the critical role of TRAF4 in bone formation and could not only improve the clinical use of MSCs in tissue engineering but also clarify the pathogenesis of bone metabolism disorders.