Rho-GEF trio regulates osteoclast differentiation and function by Rac1/Cdc42
Rho-GEF trio regulates osteoclast differentiation and function by Rac1/Cdc42
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Rho-GEF 三重奏通过 Rac1/Cdc42 调节破骨细胞分化和功能
DOI：
10.1016/j.yexcr.2020.112265
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发表时间：
2020-11-01
影响因子：
3.7
通讯作者：
Ma, Junqing
中科院分区：
文献类型：
--
作者：
Gu, Jiawen;Yang, Zhiwen;Ma, Junqing
许多骨病是由破骨细胞（OCs）骨吸收异常引起的。研究卵巢癌相关调控基因是开发新的治疗策略的必要条件。Rho gtpase已被证明可以调节OC的分化和功能，只有成熟的OC才能进行骨吸收。在这里，我们证明了Rac1和Cdc42交换因子三重功能域（Trio）对OCs引起的骨吸收至关重要。在这项研究中，我们创建了LysM-Cre；Trio（fl/fl）条件敲除小鼠，其中Trio在单核细胞中有条件消融。LysM-Cre;三重奏（fl/fl）小鼠由于骨吸收受损而导致骨量增加。此外，我们的体外分析表明，Trio条件缺乏显著抑制OC分化和功能。在分子水平上，Trio缺乏显著抑制了破骨细胞发生和OC功能的关键基因的表达。在机制上，我们的研究表明，干扰的Rac1/Cdc42-PAK1-ERK/p38信号可以用来解释CKO小鼠骨吸收能力降低。综上所述，本研究表明Trio是OCs的调节因子。研究Trio在骨关节炎中的作用为骨关节炎相关骨病的治疗提供了潜在的新见解。
Many bone diseases result from abnormal bone resorption by osteoclasts (OCs). Studying OC related regulatory genes is necessary for the development of new therapeutic strategies. Rho GTPases have been proven to regulate OC differentiation and function and only mature OCs can carry out bone resorption. Here we demonstrate that Rac1 and Cdc42 exchange factor Triple functional domain (Trio) is critical for bone resorption caused by OCs. In this study, we created LysM-Cre;Trio(fl/fl) conditional knockout mice in which Trio was conditionally ablated in monocytes. LysM-Cre;Trio(fl/fl) mice showed increased bone mass due to impaired bone resorption caused by OCs. Furthermore, our in vitro analysis indicated that Trio conditional deficiency significantly suppressed OC differentiation and function. At the molecular level, Trio deficiency significantly inhibited the expression of genes critical for osteoclastogenesis and OC function. Mechanistically, our researches suggested that perturbed Rac1/Cdc42-PAK1-ERK/p38 signaling could be used to explain the lower ability of bone resorption in CKO mice. Taken together, this study indicates that Trio is a regulator of OCs. Studying the role of Trio in OCs provides a potential new insight for the treatment of OC related bone diseases.