Key Takeaways & Executive Findings
- •• nZnO promotes osteogenic differentiation and bone regeneration by activating autophagy via the AMPK/ULK1 signaling pathway. • The combination of nZnO and mesenchymal stem cells in GelMA scaffolds significantly enhances bone repair in calvarial defect models. • Inhibition of AMPK with Compound C reverses nZnO-induced autophagy and osteogenic effects, confirming pathway specificity. • These findings propose nZnO as a promising therapeutic agent for bone defect repair, offering a novel strategy in bone tissue engineering.
Abstract
Background Nano-zinc oxide (nZnO) has attracted significant attention in bone tissue engineering due to its antibacterial properties, anti-inflammatory effects, biocompatibility, and chemical stability. Although numerous studies have demonstrated the enhancement of osteogenic differentiation by nZnO-modified tissue engineering materials, the underlying mechanisms remain poorly characterized. Methods This study aimed to identify the molecular mechanisms how nZnO promoted osteogenic differentiation and bone regeneration using transcriptome analysis, drug intervention, and shRNA knockdown techniques, etc. First, the study evaluated the in vivo effects of gelatin methacryloyl (GelMA) containing nZnO on bone regeneration using a mouse calvarial defect model. The impact of nZnO exposure on the osteogenic differentiation of mesenchymal stem cells (MSCs) was then assessed. The combined treatment of nZnO and MSCs in GelMA for bone regeneration was assessed in the mouse calvarial defect model thereafter. Results nZnO induced osteoblastic differentiation to promote bone regeneration. nZnO activated the AMP-dependent protein kinase (AMPK)-ULK1 signals to stimulate autophagosomes formation and facilitate autophagy flow, which was the essential pathway to induce osteogenic differentiation. The combined treatment of MSCs and nZnO significantly enhanced bone regeneration in calvarial defect mice. Conversely, AMPK inhibitor Compound C (C.C) reversed the effects on autophagy flow and osteogenic potentiality induced by nZnO. Conclusions These results highlight that nZnO can regulate bone regeneration by activating autophagy through the AMPK/ULK1 signaling pathway, which may provide a novel therapeutic strategy for addressing bone defects using nZnO.
1. Introduction
The incidence of bone defects has been increasing during the last decades, leading to substantial social and financial burden [1, 2]. Autologous or allogeneic bone transplantation stands as the gold standard treatment for such defects. However, this approach faces limitations due to the scarcity of donor bone and the potential risks of immune system infection and rejection [3]. Bone tissue engineering strategies, employing scaffolds, bioactive molecules, and stem cells, have gathering considerable attention as alternative approaches to promote bone regeneration [4].
Nanomaterials have emerged as highly promising candidates in bone tissue engineering, owing to their unique chemical and physical properties [5]. Nano-zinc oxide (nZnO) is one promising antibacterial inorganic material due to its antibacterial, anti-inflammatory, biocompatible, and chemically stable properties [6–11]. Furthermore, nZnO had also been considered as a good tissue engineering material with its anti-cancer, drug delivery and biological imaging activities [12]. It has been found that the incorporation of nZnO into scaffolds enhanced the attachment, diffusion, proliferation, and permeation of cells [13], with good biocompatibility, bone conductivity, and antibacterial properties [14]. However, the mechanism through which nZnO accelerates bone growth and mineralization remains unknown.
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Xiu Chen, Zhenkun Weng, Hongchao Zhang, Jian Jiao, Jingjia Liang, Jin Xu, Dongmei Wang, Qian Liu, Qing Yan, Aihua Gu (2026). Nano-zinc oxide (nZnO) targets the AMPK-ULK1 pathway to promote bone regeneration. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04322-5
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Frequently Asked Questions
What is the role of nano-zinc oxide (nZnO) in bone regeneration?
nZnO promotes bone regeneration by inducing osteogenic differentiation of mesenchymal stem cells through activation of the AMPK-ULK1 signaling pathway, which stimulates autophagy.
How does nZnO activate autophagy?
nZnO activates the AMPK-ULK1 signaling pathway, leading to autophagosome formation and enhanced autophagy flow, which is essential for its osteogenic effects.
What experimental models were used in this study?
The study used a mouse calvarial defect model to evaluate in vivo bone regeneration, and in vitro assays with mesenchymal stem cells to assess osteogenic differentiation.
What is the significance of the AMPK inhibitor Compound C in this research?
Compound C, an AMPK inhibitor, reversed the effects of nZnO on autophagy and osteogenic differentiation, confirming that the AMPK/ULK1 pathway is the key mechanism.
What are the potential clinical applications of this finding?
The findings suggest that nZnO could be used as a therapeutic agent in bone tissue engineering to enhance bone repair, offering a novel strategy for treating bone defects.
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