Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-κB and Akt pathways
Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-κB and Akt pathways
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DOI：
10.1016/j.ejphar.2007.11.013
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发表时间：
2008-02-02
影响因子：
5
通讯作者：
Okamoto, Kuniaki
中科院分区：
文献类型：
--
作者：
Hu, Jin-Ping;Nishishita, Kazuhisa;Okamoto, Kuniaki
小檗碱是一种从多种药用植物中分离得到的异喹啉类生物碱，具有抗菌、抗炎和抗肿瘤的作用。虽然小檗碱也抑制破骨细胞生成和骨吸收，其抑制作用的分子机制仍然未知。本研究旨在探讨小檗碱对核因子-κ B受体激活剂（NF-κ B）配体（RANKL）诱导的破骨细胞生成和存活的抑制作用。小檗碱抑制RANKL介导的破骨细胞的形成和存活，而对骨髓巨噬细胞或成骨细胞没有细胞毒性作用。小檗碱通过抑制I kappa B α激酶激活环的磷酸化、I kappa B α的磷酸化和降解以及NF-κ B p65核转位来减弱RANKL诱导的NF-κ B B激活。小檗碱强烈抑制RANKL诱导的Akt磷酸化;然而，药物既不抑制单核细胞/巨噬细胞集落刺激因子（M-CSF）诱导的Akt活化，也不抑制胰岛素诱导的Akt活化。在去M-CSF和RANKL的条件下，小檗碱增加破骨细胞中caspase-3的活性形式。相比之下，黄连素没有增强半胱天冬酶-3在M-CSF剥夺骨髓巨噬细胞的激活。这些发现表明，小檗碱通过抑制NF-κ B和Akt活化来抑制破骨细胞的形成和存活，并且破骨细胞谱系中的两种途径对小檗碱治疗高度敏感。(C)2007 Elsevier B. V.保留所有权利。
Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor kappa B (NF-kappa B) ligand (RANKL)induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast fort-nation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-kappa B through inhibiting phosphorylation at the activation loop of I kappa B alpha kinase, phosphorylation and degradation of I kappa B alpha, and NF-kappa B p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-kappa B and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment. (C) 2007 Elsevier B.V. All rights reserved.