Gao Xiaomeng, Xue Yiyuan, Zhu Zhou, Chen Junyu, Liu Yanhua, Cheng Xinting, Zhang Xin, Wang Jian, Pei Xibo, Wan Qianbing
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
ACS Appl Mater Interfaces. 2021 Jan 13;13(1):97-111. doi: 10.1021/acsami.0c15945. Epub 2020 Dec 23.
Zeolitic imidazolate framework-8 (ZIF-8) is an important type of metal organic framework and has found numerous applications in the biomedical field. Our previous studies have demonstrated that nano ZIF-8-based titanium implants could promote osseointegration; however, its osteogenic capacity and the related mechanisms in bone regeneration have not been fully clarified. Presented here is a nanoscale ZIF-8 that could drive rat bone mesenchymal stem cell (rBMSC) differentiation into osteoblasts both in vitro and in vivo, and interestingly, nano ZIF-8 exhibited a better osteogenic effect compared with ionic conditions of Zn at the same concentration of Zn. Moreover, the cellular uptake mechanisms of the nanoparticles were thoroughly clarified. Specifically, nano ZIF-8 could enter the rBMSC cytoplasm probably via caveolae-mediated endocytosis and macropinocytosis. The intracellular and extracellular Zn released from nano ZIF-8 and the receptors involved in the endocytosis may play a role in inducing activation of key osteogenic pathways. Furthermore, through transcriptome sequencing, multiple osteogenic pathways were found to be upregulated, among which nano ZIF-8 primarily phosphorylated ERK, thus activating the canonical mitogen-activated protein kinase pathway and promoting the osteogenesis of rBMSCs. Taken together, this study helps to elucidate the mechanism by which nano ZIF-8 regulates osteogenesis and suggests it to be a potential biomaterial for constructing multifunctional composites in bone tissue engineering.
沸石咪唑酯骨架结构-8（ZIF-8）是金属有机骨架结构的一种重要类型，已在生物医学领域得到广泛应用。我们之前的研究表明，基于纳米ZIF-8的钛植入物可促进骨整合；然而，其在骨再生中的成骨能力及相关机制尚未完全阐明。本文展示了一种纳米级ZIF-8，它在体外和体内均可促使大鼠骨髓间充质干细胞（rBMSC）分化为成骨细胞，有趣的是，在相同锌浓度下，纳米ZIF-8相比锌离子条件表现出更好的成骨效果。此外，还彻底阐明了纳米颗粒的细胞摄取机制。具体而言，纳米ZIF-8可能通过小窝介导的内吞作用和巨胞饮作用进入rBMSC细胞质。纳米ZIF-8释放的细胞内和细胞外锌以及内吞作用中涉及的受体可能在诱导关键成骨途径的激活中发挥作用。此外，通过转录组测序发现多个成骨途径上调，其中纳米ZIF-8主要使细胞外信号调节激酶（ERK）磷酸化，从而激活经典的丝裂原活化蛋白激酶途径并促进rBMSC的成骨作用。综上所述，本研究有助于阐明纳米ZIF-8调节成骨的机制，并表明它是骨组织工程中构建多功能复合材料的潜在生物材料。
