Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity
Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity
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DOI：
10.1016/j.phrs.2022.106513
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发表时间：
2022-10-18
影响因子：
9.3
通讯作者：
Li，Feng
中科院分区：
文献类型：
--
作者：
Dong，Yimin;Song，Kehan;Li，Feng
细胞粘连素-2是一种鸟嘌呤核苷酸交换因子，可激活ARF 1和ARF 6，ARF 1和ARF 6参与各种生物学过程，包括信号转导、细胞分化、细胞结构组织和存活。然而，有一个缺乏的证据表明，破骨细胞分化和骨质疏松症的发展中的细胞粘连素-2的作用。在这项研究中，我们发现细胞粘连素-2和ARF 1正调控破骨细胞的分化和功能。用SecinH 3或通过细胞粘连蛋白-2的遗传沉默来阻断细胞粘连蛋白-2/ARF 1轴可以抑制体外破骨细胞的形成和功能。SecinH 3的体内治疗改善了卵巢切除术诱导的骨质疏松症。RNA测序结合分子生物学方法揭示了cythohesin-2/ARF 1轴在破骨细胞分化中的调节作用主要依赖于激活JNK通路。此外，除了IRE 1通过其激酶活性激活JNK的常见观点外，我们发现JNK可以作用于上游并调节IRE 1的内切核糖核酸酶活性以促进XBP 1剪接。SecinH 3和cytohesin-2的沉默抑制JNK活化和IRE 1核糖核酸内切酶活性，导致破骨细胞分化的抑制。综上所述，我们的研究结果增加了对JNK和IRE 1之间的调节的新见解，并揭示了抑制cytohesin-2/ARF 1/JNK/IRE 1轴可能代表治疗绝经后骨质疏松症的潜在新策略。
cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.