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

Abstract

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 2+ . 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 2+ 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.

A periodontal tissue regeneration strategy via biphasic release of zeolitic imidazolate framework-8 and FK506 using a uniaxial electrospun Janus nanofiber

“…53 Simultaneously, previous studies have confirmed that ZIF-8 NPs could effectively improve the osteogenic function of related cells by activating MAPK signaling. 54 As expected, the PPZF JNF showed the most significant osteoconductive ability compared to the other groups. This phenomenon could be explained by the fact that in addition to promoting the osteogenesis, FK506 can also reduce the expression of pro-inflammatory factors to alleviate the inflammatory response, which helps establish a stable environment for bone rebuilding.…”

Enhanced Bone Regeneration Using a ZIF‐8‐Loaded Fibrin Composite Scaffold

“…Previous studies have confirmed that Zn 2+ improves the osteogenic function of cells by activating multiple pathways, such as the canonical Wnt pathway (WNT), mitogen‐activated protein kinase (MAPK), and protein kinase B (AKT) pathways. [ 41 ] However, the mechanisms underlying the osteogenic effects of ZIF‐8 have not been fully elucidated, and further work is required ( Figure 7 ).…”

Layered Double Hydroxide Modified Bone Cement Promoting Osseointegration via Multiple Osteogenic Signal Pathways

“…Because GO and KEGG analyses (Figure b,c) are predictable based on specific algorithms, Ingenuity Pathway Analysis (IPA, v01-04, QIANGEN Redwood City, CA, USA) software was utilized to reveal the true experimentally verified signal pathways and create the molecular interaction network (Figure d,e). Figure d shows that PMMA&LDH activated the p38 MAPK, extracellular signal-regulated kinases (ERK)/MAPK, , FGF, and TGF-β signaling, all of which promote the osteogenic differentiation of hBMSCs. Additionally, Figure e vividly demonstrates the molecular interaction network and subcellular localization of differentially expressed genes involved in osteogenesis-related signal pathways.…”