Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis.
Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis.
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DOI：
10.1038/cddis.2017.394
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发表时间：
2017-09-07
影响因子：
9
通讯作者：
Su J
中科院分区：
文献类型：
--
作者：
Chen X;Zhi X;Cao L;Weng W;Pan P;Hu H;Liu C;Zhao Q;Zhou Q;Cui J;Su J
绝经后骨质疏松症（POMP）是一种以骨密度降低和骨折风险增加为特征的公共卫生问题。过度激活的破骨细胞生成在POMP中起着至关重要的作用。本研究以sophocarpine为基础，开发了一种新的生物活性化合物MASM （M19）。虽然在体外对骨髓间充质干细胞（BMSCs）的成骨和脂肪生成无明显影响，但在体外可通过抑制NF-κB、MAPKs和PI3K/Akt通路显著抑制RANKL/M-CSF诱导的破骨细胞生成，在体内可改善去卵巢小鼠的骨质流失。核糖体蛋白s5 （RPS5）已被确定为M19的靶点，并调节破骨细胞发生过程中的PI3K/Akt、NF-κB和MAPKs通路。过表达RPS5可与M19协同抑制破骨细胞的形成，而沉默RPS5则会削弱M19对体外破骨细胞形成的抑制作用。在这三条通路中，Akt在M19的作用中起主要作用。Akt激活剂SC79部分逆转了M19和rps5敲低对破骨细胞形成的抑制作用。这表明RPS5是抑制破骨细胞生成和骨质疏松症治疗的潜在候选靶点，M19是POMP治疗的有前景的药物。
Postmenopausal osteoporosis (POMP) is a public health problem characterized by decreased bone density and increased fracture risk. Over-activated osteoclastogenesis plays a vital role in POMP. Here we developed a novel bioactive compound MASM (M19) based on sophocarpine. Although it showed no significant effects on osteogenesis and adipogenesis for bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, it could significantly inhibit RANKL/M-CSF induced osteoclastogenesis through suppressing NF-κB, MAPKs and PI3K/Akt pathways in vitro and ameliorate bone loss in ovariectomized mice in vivo. Ribosomal protein s5 (RPS5) has been identified as a target of M19 and regulates PI3K/Akt, NF-κB and MAPKs pathways in osteoclastogenesis. Overexpressions of RPS5 synergistically inhibited osteoclastogenesis with M19 while silencing RPS5 compromised M19 inhibitory effects on osteoclastogenesis in vitro. Among the three pathways, Akt plays a major role in M19 effects. The Akt activator SC79 partially reversed the inhibitory effects on osteoclastogenesis by M19 and RPS5-knocking-down. It indicates that RPS5 serves as a potential candidate target for inhibiting osteoclastogenesis and osteoporosis therapy and M19 is a promising agent for POMP treatment.
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