Regulating macrophage glucose metabolism homeostasis via mitochondrial rheostats by short fiber-microsphere scaffolds for bone repair
: Zhuang, Pengzhen; Chen, Yu; Zhang, Yu; Yang, Wu; Zuo, Guilai; Rosenholm, Jessica M.; Wang, Zhongmin; Wang, Juan; Cui, Wenguo; Zhang, Hongbo
Publisher: KEAI PUBLISHING LTD
: BEIJING
: 2025
Bioactive Materials
: BIOACTIVE MATERIALS
: BIOACT MATER
: 49
: 399
: 417
: 19
: 2452-199X
DOI: https://doi.org/10.1016/j.bioactmat.2025.03.008
: https://doi.org/10.1016/j.bioactmat.2025.03.008
: https://research.utu.fi/converis/portal/detail/Publication/491809631
The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis. The restoration of mitochondrial homeostasis, serving as a pivotal rheostat for balancing glucose metabolism in immune cells, can effectively mitigate inflammation and initiate osteogenesis. Herein, an ion-activated mitochondrial rheostat fiber-microsphere polymerization system (FM@CeZnHA) was innovatively constructed. Physical-chemical and molecular biological methods confirmed that CeZnHA, characterized by a rapid degradation rate, releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions. This process reduces the glycolysis level of macrophages by down-regulating the NF-kappa B p65 signaling pathway, enhances their mitochondrial metabolic dependence, alleviates excessive early inflammatory responses, and promptly initiates osteogenesis. The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment, continuously restoring mitochondrial homeostasis and accelerating ossification center formation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions. This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
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Pengzhen Zhuang and Yu Chen contributed equally to this work. This work was supported by the Program of Shanghai Academic/Technology Research Leader (22XD1422600), the Research Fellow (Grant No.353146), Research Project (347897), Solution for Health Profile (336355), InFLAMES Flagship (337531) grants and Printed Intelligence Infrastructure" (PII-FIRI) from Research Council of Finland. This study is part of the activities of the Åbo Akademi University Foundation (SÅA) funded Center of Excellence in Research "Materials-driven solutions for combating antimicrobial resistance (MADNESS)" at ÅAU.
