Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2
Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2
复制标题
抑制 PRMT5 可抑制破骨细胞分化，并通过下调 CXCL10 和 RSAD2 部分防止卵巢切除引起的骨质流失。
DOI：
10.1016/j.cellsig.2017.03.004
复制
发表时间：
2017-06-01
影响因子：
4.8
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Dong, Yonghui;Song, Chao;Li, Feng
蛋白精氨酸甲基转移酶5（PRMT5）是一种精氨酸甲基化甲基转移酶，可调节多种生理过程。在炎症和多种癌症中已报道PRMT5活性异常。由于破骨细胞分化的特征是炎症相关通路的激活，我们推测PRMT5可能在此过程中起作用。在本研究中，我们发现破骨细胞分化过程中PRMT5表达上调。用小干扰RNA（siRNA）敲低骨髓单核细胞（BMMs）中的PRMT5，导致核因子-κB受体激活剂配体（RANKL）诱导的破骨细胞形成受到抑制。与PRMT5敲低结果一致，PRMT5抑制剂EPZ015666（EPZ）抑制破骨细胞分化和骨吸收。腹腔注射EPZ可防止卵巢切除诱导的骨质流失。此外，EPZ抑制RANKL诱导的核因子-κB（NF - κB）和丝裂原活化蛋白激酶（MAPK）的激活。表达微阵列显示，EPZ处理改变了几个破骨细胞形成相关基因的表达，包括趋化因子C - X - C基序配体10（CXCL10）。给予重组CXCL10可部分逆转PRMT5抑制剂对破骨细胞生成的抑制作用。有趣的是，当PRMT5被抑制时，据报道为抗病毒蛋白的RSAD2明显受到抑制。用siRNA敲低BMMs中的RSAD2导致破骨细胞分化受到抑制。随后的染色质免疫沉淀-定量聚合酶链反应（ChIP - qPCR）表明，PRMT5抑制和敲低均导致CXCL10和RSAD2启动子处的H3R8或/和H4R3甲基化降低。总之，我们的研究发现PRMT5是破骨细胞分化的激活剂，抑制PRMT5可通过下调CXCL10和RSAD2部分抑制破骨细胞生成。（C）2017作者。由爱思唯尔公司出版。
Protein arginine methyltransferase 5 (PRMT5) is an arginine methylation methyltransferase that regulates various physiological processes. Abnormal PRMT5 activity has been reported in inflammation and various types of cancers. Because osteoclast differentiation is characterized by the activation of inflammation-related pathways, we speculated that PRMT5 may play a role in this process. In the present study, we found that PRMT5 was upregulated during osteoclast differentiation. Knockdown of PRMT5 with siRNA in bone marrow mononuclear cells (BMMs) resulted in inhibition of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast formation. Consistent with the PRMT5 knockdown results, the PRMT5 inhibitor EPZ015666 (EPZ) suppressed osteoclast differentiation and bone resorption. Intraperitoneal administration of EPZ prevented ovariectomy-induced bone loss. Moreover, RANKL-induced NF-kB and MAPK activation was inhibited by EPZ. Expression microarrays showed that the expression of several osteoclast formation-related genes was altered by EPZ treatment, including chemokine C-X-C motif ligand 10 (CXCL10). Administration of recombinant CXCL10 partially reversed the osteoclastogenesis inhibition effect of the PRMT5 inhibitor. Intriguingly, RSAD2, which is a reported antiviral protein, was apparently suppressed when PRMT5 was inhibited. Knockdown of RSAD2 with siRNA in BMMs led to inhibition of osteoclast differentiation. Subsequent ChIP-qPCR identified that both PRMT5 inhibition and knockdown resulted in decreased H3R8 or/and H4R3 methylation at CXCL10 and RSAD2 promotors. In conclusion, our study found that PRMT5 is an activator of osteoclast differentiation and inhibition of PRMT5 partially suppressed osteoclastogenesis through downregulation of CXCL10 and RSAD2. (C) 2017 The Authors. Published by Elsevier Inc.