Inhibiting Monoacylglycerol Lipase Suppresses RANKL-Induced Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss.
Inhibiting Monoacylglycerol Lipase Suppresses RANKL-Induced Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss.
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抑制单酰甘油脂肪酶可抑制 RANKL 诱导的破骨细胞生成并减轻卵巢切除术引起的骨质流失
DOI：
10.3389/fcell.2021.640867
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发表时间：
2021
影响因子：
5.5
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Liu H;Zhou C;Qi D;Gao Y;Zhu M;Tao T;Sun X;Xiao J
骨质疏松症是一种常见的慢性代谢性骨病，其特征是骨小梁减少，骨脆性增加。单酰基甘油脂肪酶(MAGL)是一种脂肪分解酶，能催化单甘酯的水解，并特异性地降解2-花生四烯基甘油(2-AG)。以往的研究表明，2-AG是花生四烯酸的主要来源，也是大麻素受体中含量最丰富的内源性激动剂。考虑到炎症介质/大麻素受体与骨代谢的密切关系，我们推测MAGL可能在破骨细胞分化中发挥作用。在本研究中，我们发现MAGL蛋白在破骨细胞分化过程中表达增加。腺病毒介导的shRNA在骨髓来源的巨噬细胞中敲除MAGL，证实了MAGL对破骨细胞形成和骨吸收的抑制作用。此外，JZL184对MAGL的药理抑制抑制了破骨细胞分化、骨吸收和破骨细胞特异性基因的表达。丝裂原活化蛋白激酶(MAPK)和核因子κB(NF-κB)通路的激活被JZL184和MAGL缺失所抑制。我们的体内研究表明，JZL184改善了去卵巢小鼠模型的骨丢失。此外，H1Calponin的过表达可部分缓解JZL184或MAGL缺失对破骨细胞生成的抑制作用。因此，我们认为，靶向MAGL可能是治疗骨质疏松症的一种新策略。
Osteoporosis is a common chronic metabolic bone disease characterized by reduced trabecular bone and increased bone fragility. Monoacylglycerol lipase (MAGL) is a lipolytic enzyme to catalyze the hydrolysis of monoglycerides and specifically degrades the 2-arachidonoyl glycerol (2-AG). Previous studies have identified that 2-AG is the mainly source for arachidonic acid and the most abundant endogenous agonist of cannabinoid receptors. Considering the close relationship between inflammatory mediators/cannabinoid receptors and bone metabolism, we speculated that MAGL may play a role in the osteoclast differentiation. In the present study, we found that MAGL protein expression increased during osteoclast differentiation. MAGL knockdown by adenovirus-mediated shRNA in bone marrow-derived macrophages demonstrated the suppressive effects of MAGL on osteoclast formation and bone resorption. In addition, pharmacological inhibition of MAGL by JZL184 suppressed osteoclast differentiation, bone resorption, and osteoclast-specific gene expression. Activation of the Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways was inhibited by JZL184 and deletion of MAGL. Our in vivo study indicated that JZL184 ameliorated bone loss in an ovariectomized mouse model. Furthermore, overexpressing H1 calponin partially alleviated the inhibition caused by JZL184 or MAGL deletion on osteoclastogenesis. Therefore, we conclude that targeting MAGL may be a novel therapeutic strategy for osteoporosis.
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影响因子：
3.5
作者：
Liu R;Jin JP
通讯作者：
Jin JP
影响因子：
64.5
作者：
Nomura DK;Long JZ;Niessen S;Hoover HS;Ng SW;Cravatt BF
通讯作者：
Cravatt BF
DOI：
10.1007/s00018-018-2817-9
发表时间：
2018-07
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
通讯作者：
--
单酰基甘油脂肪酶抑制剂 JZL184 可降低大鼠骨骼肌挫伤的炎症反应。
影响因子：
5
作者：
Jiang, Shu-Kun;Zhang, Miao;Guan, Da-Wei
通讯作者：
Guan, Da-Wei
影响因子：
13.5
作者：
Grabner GF;Zimmermann R;Schicho R;Taschler U
通讯作者：
Taschler U