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Neobavaisoflavone inhibits osteoclastogenesis through blocking RANKL signalling-mediated TRAF6 and c-Src recruitment and NF-κB, MAPK and Akt pathways.
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2020-06-30 , DOI: 10.1111/jcmm.15543
Huiwen Chen 1 , Chao Fang 1 , Xin Zhi 1, 2 , Shaojun Song 1 , Yanqiu Gu 3 , Xiaofei Chen 4 , Jin Cui 1 , Yan Hu 1 , Weizong Weng 1 , Qirong Zhou 1 , Yajun Wang 1 , Yao Wang 1 , Hao Jiang 1 , Xiaoqun Li 1, 2 , Liehu Cao 5 , Xiao Chen 1, 6 , Jiacan Su 1, 7
Affiliation  

Psoralea corylifolia (P corylifolia ) has been popularly applied in traditional Chinese medicine decoction for treating osteoporosis and promoting fracture healing since centuries ago. However, the bioactive natural components remain unknown. In this study, applying comprehensive two‐dimensional cell membrane chromatographic/C18 column/time‐of‐flight mass spectrometry (2D CMC/C18 column/TOFMS) system, neobavaisoflavone (NBIF), for the first time, was identified for the bioaffinity with RAW 264.7 cells membranes from the extracts of P corylifolia . Here, we revealed that NBIF inhibited RANKL‐mediated osteoclastogenesis in bone marrow monocytes (BMMCs) and RAW264.7 cells dose dependently at the early stage. Moreover, NBIF inhibited osteoclasts function demonstrated by actin ring formation assay and pit‐formation assay. With regard to the underlying molecular mechanism, co‐immunoprecipitation showed that both the interactions of RANK with TRAF6 and with c‐Src were disrupted. In addition, NBIF inhibited the phosphorylation of P50, P65, IκB in NF‐κB pathway, ERK, JNK, P38 in MAPKs pathway, AKT in Akt pathway, accompanied with a blockade of calcium oscillation and inactivation of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In vivo, NBIF inhibited osteoclastogenesis, promoted osteogenesis and ameliorated bone loss in ovariectomized mice. In summary, P corylifolia‐derived NBIF inhibited RANKL‐mediated osteoclastogenesis by suppressing the recruitment of TRAF6 and c‐Src to RANK, inactivating NF‐κB, MAPKs, and Akt signalling pathways and inhibiting calcium oscillation and NFATc1 translocation. NBIF might serve as a promising candidate for the treatment of osteoclast‐associated osteopenic diseases.

中文翻译:


新巴伐利亚异黄酮通过阻断 RANKL 信号介导的 TRAF6 和 c-Src 募集以及 NF-κB、MAPK 和 Akt 途径来抑制破骨细胞生成。



补骨脂Pcorylifolia )自数百年前就被广泛应用于中药汤剂中,用于治疗骨质疏松症和促进骨折愈合。然而,生物活性天然成分仍然未知。本研究应用综合二维细胞膜色谱/C18柱/飞行时间质谱(2D CMC/C18柱/TOFMS)系统,首次鉴定了新木薯异黄酮(NBIF)与来自P corylifolia提取物的 RAW 264.7 细胞膜。在这里,我们发现 NBIF 在早期剂量依赖性地抑制骨髓单核细胞 (BMMC) 和 RAW264.7 细胞中 RANKL 介导的破骨细胞生成。此外,肌动蛋白环形成试验和凹坑形成试验证明,NBIF 抑制破骨细胞功能。关于潜在的分子机制,免疫共沉淀显示 RANK 与 TRAF6 和 c-Src 的相互作用都被破坏。此外,NBIF抑制NF-κB通路中的P50、P65、IκB,MAPKs通路中的ERK、JNK、P38,Akt通路中的AKT的磷酸化,并伴有钙振荡的阻断和活化的核因子的核转位失活。 T 细胞胞质 1 (NFATc1)。在体内,NBIF 抑制卵巢切除小鼠的破骨细胞生成,促进骨生成并改善骨质流失。总之, P corylifolia衍生的 NBIF 通过抑制 TRAF6 和 c-Src 向 RANK 的募集、失活 NF-κB、MAPK 和 Akt 信号通路以及抑制钙振荡和 NFATc1 易位来抑制 RANKL 介导的破骨细胞生成。 NBIF 可能成为治疗破骨细胞相关骨质减少疾病的有前途的候选药物。
更新日期:2020-08-11
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