Nanoscale Zeolitic Imidazolate Framework-8 Activator of Canonical MAPK Signaling for Bone Repair

• Published in: ACS applied materials & interfaces 2021-01, Vol.13 (1), p.97-111
• Main Authors: Gao, Xiaomeng, Xue, Yiyuan, Zhu, Zhou, Chen, Junyu, Liu, Yanhua, Cheng, Xinting, Zhang, Xin, Wang, Jian, Pei, Xibo, Wan, Qianbing
• Format: Article
• Language: English
• Subjects: Alginates - chemistry; Animals; Bone and Bones - cytology; Bone and Bones - injuries; Bone Regeneration - drug effects; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Drug Carriers - chemistry; Endocytosis - physiology; Hydrogels - chemistry; Male; MAP Kinase Signaling System - drug effects; Mesenchymal Stem Cells - drug effects; Metal-Organic Frameworks - chemical synthesis; Metal-Organic Frameworks - metabolism; Metal-Organic Frameworks - therapeutic use; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Osteoblasts - cytology; Osteogenesis - drug effects; Pinocytosis - physiology; Rats; Rats, Sprague-Dawley; Zinc - chemistry; Zinc - metabolism
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.0c15945

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.