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首页> 外文学位 >Epimedium Active Component Icaritin Enhances Bone Mass through Regulating the Coupling of Bone Formation and Resorption Mediated by Distinct Signaling Targets
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Epimedium Active Component Icaritin Enhances Bone Mass through Regulating the Coupling of Bone Formation and Resorption Mediated by Distinct Signaling Targets

机译：淫羊med活性成分伊立肽通过调节不同信号靶标介导的骨形成和吸收的耦合来增强骨量。

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摘要

Osteoporosis is a skeletal disease characterized by low bone mass and increased risk of fracture. There has been a long term interest in searching novel natural products for the prevention and treatment of osteoporosis. Using in vitro and in vivo systems, we investigated the therapeutic efficacy and molecular mechanisms of Icaritin, an active component from Epimedium (Berberidaceae), on the treatment of osteoporosis. Our results showed that Icaritin promoted osteoblast differentiation indexed by increased alkaline phosphatase (ALP) activity, mineralized nodule formation and upregulated osteogenic maker genes expression. Icaritin enhanced bone acquisition in the calvaria organ culture compared with the controls. Molecular examination showed that Icaritin elevated Smad1/5/8 phosphorylation in osteoblast, while this effect was suppressed by Noggin and siRNA mediated BMPR-II knockdown. Immunofluorescence staining indicated that Icaritin induced BMPR-II endocytosis in association with clathrin. We next identified the ligand-protein binding of Icaritin and BMPR-II using a fluorescence-based thermal shift assay. The result showed that Icaritin affected the BMPR-II thermal stability in a concentration dependent manner, suggests a direct interaction between Icaritin and BMPR-II. These observations suggest that Icaritin may activate the BMP/Smad1 signaling by binding to BMPR-II and increasing its endocytosis in osteoblast. In the osteoclast differentiation model, Icaritin was found to inhibit osteoclast by significantly decreased numbers of tartrate-resistant acid phosphatase (TRAP) positive multi-nucleated cells, disruption of actin-ring, and eliminated bone resorptive activity compared with the controls. Icaritin performed these effects by inducing mature osteoclasts apoptosis without affect their early differentiation. The Icaritin-induced mature osteoclasts apoptosis was mediated by the c-src/Akt signaling but not through the activation of Smad1/5/8, indicating that Icaritin exerts a differential mode of signaling mechanism in osteoclast compared to that observed in osteoblast. In the in vivo system, we found that Icaritin treatment prevented bone loss and maintained the biomechanical properties of the femurs in ovariectomy (OVX) induced mouse osteoporosis model. Osteogenic marker genes were upregulated by Icaritin treatment compared with that in the sham and the OVX groups. Our results suggest that Icaritin promotes osteoblast differentiation and bone formation mediated by the BMP/Smad1 signaling, while inhibits osteoclast bone resorption function by inducing mature osteoclasts apoptosis via the c-src/Akt signaling. Icaritin may serve as a potential therapeutic agent for the treatment of osteoporosis through enhancing the osteoblast anabolic effect and inhibiting the osteoclast functions mediated by distinct signaling targets.
机译：骨质疏松症是一种骨骼疾病，其特征是骨量低和骨折风险增加。人们一直在寻找用于预防和治疗骨质疏松症的新型天然产物。使用体外和体内系统，我们研究了淫羊med（小B科）的活性成分伊卡瑞汀的治疗功效和分子机制，用于治疗骨质疏松症。我们的结果表明，叶黄素通过碱性磷酸酶（ALP）活性增加，矿化结节形成和成骨制造基因表达上调来促进成骨细胞分化。与对照相比，伊卡瑞汀增强了颅盖器官培养物中的骨获取。分子检查表明，伊卡立肽可提高成骨细胞中Smad1 / 5/8的磷酸化，而Noggin和siRNA介导的BMPR-II敲低可抑制这种作用。免疫荧光染色表明，叶绿素与网格蛋白相关地诱导了BMPR-II的内吞作用。接下来，我们使用基于荧光的热位移测定法鉴定了伊卡肽和BMPR-II的配体-蛋白质结合。结果表明，伊卡肽素以浓度依赖的方式影响BMPR-II的热稳定性，表明伊卡肽素与BMPR-II之间存在直接相互作用。这些观察结果表明，叶抑素可通过结合BMPR-II并增加其在成骨细胞中的内吞作用而激活BMP / Smad1信号传导。在破骨细胞分化模型中，与对照组相比，发现伊立肽通过抑制酒石酸抗性酸性磷酸酶（TRAP）阳性多核细胞数量，破坏肌动蛋白环并消除骨吸收活性来抑制破骨细胞。伊卡肽通过诱导成熟的破骨细胞凋亡而发挥了这些作用，而并不影响它们的早期分化。伊立肽诱导的成熟破骨细胞凋亡是由c-src / Akt信号传导介导的，而不是通过Smad1 / 5/8的激活介导的，这表明与成骨细胞相比，伊立肽在破骨细胞中发挥了不同的信号传导机制。在体内系统中，我们发现伊立肽治疗可以防止骨丢失，并在卵巢切除术（OVX）诱发的小鼠骨质疏松模型中保持股骨的生物力学特性。与假手术组和OVX组相比，伊卡肽素处理使成骨标记基因上调。我们的结果表明，叶黄素促进由BMP / Smad1信号传导介导的成骨细胞分化和骨形成，同时通过c-src / Akt信号传导诱导成熟的破骨细胞凋亡，从而抑制破骨细胞的骨吸收功能。伊立肽可以通过增强成骨细胞的合成代谢作用并抑制由不同信号靶介导的破骨细胞功能，作为治疗骨质疏松症的潜在治疗剂。

著录项

  • 作者

    Lu, Li.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Health education.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 209 p.
  • 总页数 209
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:46:37

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