Licorice isoliquiritigenin-encapsulated mesoporous silica nanoparticles for osteoclast inhibition and bone loss prevention
Licorice isoliquiritigenin-encapsulated mesoporous silica nanoparticles for osteoclast inhibition and bone loss prevention
复制标题
甘草异甘草素封装介孔二氧化硅纳米颗粒用于抑制破骨细胞和预防骨质流失
DOI：
10.7150/thno.33376
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Peng, Bin
中科院分区：
文献类型：
--
作者：
Sun, Xiaoyue;Zhang, Jie;Peng, Bin
介孔二氧化硅纳米颗粒(MSN)广泛应用于骨组织再生和局部给药。然而，MSN单独对破骨细胞形成和功能的影响，以及利用MSNS递送天然分子抗骨吸收的作用仍未被探索。在此，我们报道了甘草衍生生物活性黄酮异甘草素(ISL)包裹的MSNS(MSNS-ISL)作为一种有效的骨生物响应性纳米胶囊系统的研究进展，以防止体外和体内破骨细胞介导的骨丢失。方法：合成MSNS-ISL纳米粒，考察其载药和释药特性。以小鼠原代骨髓来源的巨噬细胞为材料，进行破骨细胞分化和骨吸收的体外实验。采用脂多糖(LPS)介导的颅骨侵蚀模型进行动物体内实验。结果：合成的MSNS-ISL为球形，高度单分散，具有较大的比表面积和良好的生物相容性，并允许酸敏感的药物释放。与游离ISL和MSNS单独作用相比，MSNS-ISL显著和相加地抑制核因子受体激活剂κB配体(RANKL)诱导的破骨细胞生成，缩小封闭区的大小和数量，降低体外破骨细胞的溶骨能力。MSNS-ISL治疗还下调RANKL刺激的破骨细胞相关基因和转录因子的mRNA表达。在机制上，MSNS-ISL显著抑制RANKL诱导的肿瘤坏死因子受体相关因子6(TRAF6)的表达、丝裂原活化蛋白激酶(MAPK)的磷酸化、κBα抑制物(IκBα)的磷酸化和降解，以及核因子-κB(NF-κB)p65和激活蛋白(AP)-1组分c-Fos的核转位。此外，MSNS-ISL几乎完全抑制活化T细胞核因子(NFATc1)的表达。与体外实验结果一致，MSNS-ISL可阻断破骨细胞活性，减轻体内炎症相关的颅骨破坏，并抑制c-Fos、NFATc1和组织蛋白酶K的表达水平。结论：甘草ISL包裹的MSN具有明显的抗破骨细胞生成作用，对炎症性骨破坏具有保护作用。我们的发现揭示了应用MSNS-ISL作为一种有效的基于天然产物的骨生物响应性纳米胶囊系统来防止破骨细胞介导的骨丢失的可行性。
Mesoporous silica nanoparticles (MSNs) are extensively used in bone tissue regeneration and local drug delivery. However, the effects of MSNs alone on osteoclast formation and function, as well as the utilization of MSNs to deliver natural molecules against bone resorption, remain unexplored. Here, we report the development of licorice-derived bioactive flavonoid isoliquiritigenin (ISL)-encapsulated MSNs (MSNs-ISL) as a potent bone-bioresponsive nanoencapsulation system for prevention of osteoclast-mediated bone loss in vitro and in vivo. Methods: We synthesized MSNs-ISL and then investigated the drug loading and release characteristics of the resulting nanoparticles. In vitro experiments on osteoclast differentiation and bone resorption were performed using mouse primary bone marrow-derived macrophages (BMMs). In vivo animal experiments were conducted using a lipopolysaccharide (LPS)-mediated calvarial bone erosion model. Results: The resulting MSNs-ISL were spherical and highly monodispersed; they possessed a large specific surface area and superior biocompatibility, and allowed acid-sensitive sustained drug release. Compared with free ISL and MSNs alone, MSNs-ISL significantly and additively inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast generation, decreased the size and quantity of sealing zones, and reduced the osteolytic capacity of osteoclasts in vitro. MSNs-ISL treatment also downregulated RANKL-stimulated mRNA expression of osteoclast-associated genes and transcription factors. Mechanistically, MSNs-ISL remarkably attenuated the RANKL-initiated expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of mitogen-activated protein kinases (MAPKs), and phosphorylation and degradation of inhibitor of κBα (IκBα), together with the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the activator protein (AP)-1 component c-Fos. Moreover, MSNs-ISL almost completely restrained the expression of nuclear factor of activated T cells (NFATc1). Consistent with the in vitro results, MSNs-ISL could block osteoclast activity; relieve inflammation-related calvarial bone destruction in vivo; and suppress c-Fos, NFATc1, and cathepsin K expression levels. Conclusion: Licorice ISL-encapsulated MSNs exhibit notable anti-osteoclastogenetic effects and protect against inflammatory bone destruction. Our findings reveal the feasibility of applying MSNs-ISL as an effective natural product-based bone-bioresponsive nanoencapsulation system to prevent osteoclast-mediated bone loss.