Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR.
Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR.
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Meclizine 部分通过上调 PXR 预防卵巢切除术引起的骨质流失并抑制破骨细胞生成
DOI：
10.3389/fphar.2017.00693
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发表时间：
2017
影响因子：
5.6
通讯作者：
Guo F
中科院分区：
文献类型：
--
作者：
Guo J;Li W;Wu Y;Jing X;Huang J;Zhang J;Xiang W;Ren R;Lv Z;Xiao J;Guo F
孕烷X受体（Pregnane X receptor，PXR）属于核激素受体超家族，在多种生物学功能中发挥重要作用，尤其是在炎症过程中。除此之外，最近的研究表明PXR对骨组织有重要影响。作为PXR的激动剂，美克洛嗪是哌嗪衍生的组胺H1拮抗剂，并且已被频繁地用于预防和治疗呕吐和恶心。由于破骨细胞生成的特点是炎症相关信号通路的激活，我们推测美克洛嗪可能影响破骨细胞的形成和功能。在本研究中，我们探讨了美克洛嗪在体内和体外对RANKL诱导的破骨细胞生成的影响。在原代骨髓源性巨噬细胞（BMCs）中，美克洛嗪以剂量依赖性方式减少破骨细胞形成和骨吸收，而用siRNA敲低PXR部分废除了美克洛嗪对破骨细胞生成的抑制。一方面，在分子水平上，美克洛嗪减弱了RANKL诱导的c-Fos、NFATc 1、核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）（包括ERK和p38，但不包括JNK）的活化。同时，美克洛嗪降低破骨细胞特异性基因的表达，包括TRAP，MMP 9，组织蛋白酶K和NFATc 1。另一方面，美克洛嗪通过抑制破骨细胞活性减少OVX诱导的骨丢失。总之，我们的结果表明，美克洛嗪通过调节几种RANKL信号通路抑制破骨细胞生成，PXR参与了该过程。因此，美克洛嗪可能被认为是一种新的治疗破骨细胞相关疾病的候选药物。
Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both in vivo and in vitro. In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.
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影响因子：
4.6
作者：
Hong CT;Chau KY;Schapira AH
通讯作者：
Schapira AH
影响因子：
9.3
作者：
Bachmann, K;Patel, H;Sambucetti, L
通讯作者：
Sambucetti, L
影响因子：
6.1
作者：
Chirulli, V;Longo, V;Gervasi, PG
通讯作者：
Gervasi, PG
影响因子：
6.5
作者：
Cho, Joo-Youn;Kang, Dong Wook;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
环氧类二十烷酸抑制破骨细胞生成并防止卵巢切除术引起的骨质流失。
影响因子：
4.8
作者：
Guan, Hanfeng;Zhao, Libo;Xiao, Jun
通讯作者：
Xiao, Jun