Mnzif-8Gelma Enhances Osteoporotic Jawbone Repair By Inhibiting Mitochondria Fission

To investigate the molecular mechanisms underlying impaired alveolar bone regeneration in osteoporotic (OP) conditions, focusing on mitochondria-mediated bone marrow mesenchymal stem cells (BMSCs) dysfunction, and to develop a novel biomaterial to enhance alveolar bone healing in OP extraction sockets. Eight-week-old female C57BL/6 mice underwent bilateral ovariectomy (OVX) to induce osteoporosis with ethical approval obtained, primary BMSCs were collected for evaluating mitochondrial function and osteogenic potential. A novel biomaterial Mn-ZIF-8@GelMAwas designed by integrating redox-active manganese ions (Mn²⁺/Mn⁴⁺) into metal-organic framework ZIF-8 and subsequently incorporated into GelMA hydrogel. RNA-sequencing transcriptome analysis explored molecular pathways, and a tooth-extraction OP model was used for in vivo validation. OVX-induced OP mouse exhibited deteriorated alveolar bone micro-architecture and impaired osteogenesis in BMSCs with elevated reactive oxygen species (ROS) levels and impaired mitochondrial function. Mn-ZIF-8@GelMAreduced excessive mitochondrial fission by down-regulating dynamin-related protein 1(DRP1) phosphorylation via mitochondrial antiviral signaling protein (MAVS) upregulation, thus normalizing mitochondrial morphology and enhancing osteogenic differentiation in OP-BMSCs. Transcriptome analysis indicated regulation of oxidative phosphorylation, cell cycle and inflammation pathways. In vivo, Mn-ZIF-8@GelMApromoted alveolar bone regeneration, increased expression of bone morphogenetic protein2(BMP-2) and MAVS in OP extraction sockets. Mn-ZIF-8@GelMA addresses OP-related mitochondrial over-fission and dysfunction, effectively enhancing bone regeneration by regulating mitochondrial dynamics and oxidative stress. This study provides a novel therapeutic strategy and biomaterial design approach for OP-related bone regeneration.