Puerarin specifically disrupts osteoclast activation via blocking integrin-β3 Pyk2/Src/Cbl signaling pathway.
Puerarin specifically disrupts osteoclast activation via blocking integrin-β3 Pyk2/Src/Cbl signaling pathway.
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葛根素通过阻断整合素-β3 Pyk2/Src/Cbl 信号通路特异性破坏破骨细胞活化
DOI：
10.1016/j.jot.2022.01.003
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Qiu Z;Li L;Huang Y;Shi K;Zhang L;Huang C;Liang J;Zeng Q;Wang J;He X;Qin L;Wang X
鉴于目前绝经后骨质疏松症的抗吸收剂的局限性，需要一种不损害骨吸收和骨形成之间的耦合串扰的替代品，即。破骨细胞生成。葛根素是一种独特的C-糖苷异黄酮类化合物，被发现能够通过抑制骨吸收来防止骨质流失，但其潜在机制存在争议。在本研究中，我们在体外研究了葛根素对破骨细胞分化、活化和骨吸收的影响及其潜在分子机制，然后利用卵巢切除（OVX）大鼠模型评估了葛根素对骨代谢的影响。在体外，在原始 264.7 细胞和小鼠 BMM 中研究了葛根素对破骨细胞的细胞毒性、分化、凋亡、激活和功能的影响。从机制上讲，通过 RT-PCR、蛋白质印迹、免疫荧光和激酶活性测定来确定破骨细胞相关标记。在体内，采用Micro-CT、组织学、血清骨生物标志物和力学测试来评价葛根素预防骨质疏松的作用。葛根素显着抑制破骨细胞活化和骨吸收，而不影响破骨细胞生成或凋亡。从机制上看，葛根素组整合素β3蛋白表达及Src、Pyk2、Cbl磷酸化水平低于对照组。口服葛根素可防止 OVX 诱导的小梁骨丢失，并显着提高大鼠的骨强度。此外，葛根素显着降低陷阱阳性破骨细胞数量和血清TRAP-5b、CTx1，而不影响骨形成率。总的来说，葛根素通过抑制破骨细胞活化和骨吸收，通过抑制整合素-β3-Pyk2/Cbl/Src信号通路来预防OVX大鼠的骨丢失，而不影响破骨细胞的形成或凋亡。这些结果证明了葛根素对骨代谢的独特作用机制，为预防绝经后骨质疏松症提供了一种新的药物。
Given the limitations of current anti-resorption agents for postmenopausal osteoporosis, there is a need for alternatives without impairing coupling crosstalk between bone resorption and bone formation ie. osteoclastogenesis. Puerarin, a unique C-glycoside isoflavonoid, was found to be able to prevent bone loss by inhibiting bone resorption, but the underlying mechanism was controversial. In this study, we investigated the effects of puerarin on osteoclastic differentiation, activation and bone resorption and its underlying molecular mechanism in vitro, and then evaluated the effects of puerarin on bone metabolism using an ovariectomized (OVX) rat model. In vitro, the effect of puerarin on osteoclastic cytotoxicity, differentiation, apoptosis, activation and function were studied in raw 264.7 cells and mouse BMMs. Mechanistically, osteoclast-related makers were determined by RT-PCR, western blot, immunofluorescence, and kinase activity assay. In vivo, Micro-CT, histology, serum bone biomarker, and mechanical testing were used to evaluate the effects of puerarin on preventing osteoporosis. Puerarin significantly inhibited osteoclast activation and bone resorption, without affecting osteoclastogenesis or apoptosis. In terms of mechanism, the expressions of protein of integrin-β3 and phosphorylations of Src, Pyk2 and Cbl were lower in puerarin group than those in the control group. Oral administration of puerarin prevented OVX-induced trabecular bone loss and significantly improved bone strength in rats. Moreover, puerarin significantly decreased trap positive osteoclast numbers and serum TRAP-5b, CTx1, without affecting bone formation rate. Collectively, puerarin prevented the bone loss in OVX rat through suppression of osteoclast activation and bone resorption, by inhibiting integrin-β3-Pyk2/Cbl/Src signaling pathway, without affecting osteoclasts formation or apoptosis. These results demonstrate the unique mechanism of puerarin on bone metabolism and provide a novel agent for prevention of postmenopausal osteoporosis.
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影响因子：
6.6
作者：
Chen SH;Wang XL;Zheng LZ;Dai Y;Zhang JY;Guo BL;Yang ZJ;Yao XS;Qin L
通讯作者：
Qin L
影响因子：
1.6
作者：
Michihara, Seiwa;Tanaka, Teruyoshi;Kawamura, Yukio
通讯作者：
Kawamura, Yukio
影响因子：
7.3
作者：
Panwar, Preety;Law, Simon;Bromme, Dieter
通讯作者：
Bromme, Dieter
影响因子：
4.2
作者：
Rissanen, Jukka P.;Suominen, Mari I.;Halleen, Jussi M.
通讯作者：
Halleen, Jussi M.
影响因子：
4.2
作者：
Kakehashi A;Yoshida M;Tago Y;Ishii N;Okuno T;Gi M;Wanibuchi H
通讯作者：
Wanibuchi H