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ISO-1 sustained-release hydrogel repairs infected bone defects by suppressing osteoblast pyroptosis and enhancing
Xiangwen Shi1,2, Mingjie Wei2, Zhe Yin1
1Kunming Medical University, Kunming, Yunan, China.
Background:
Staphylococcus aureus (SA)-induced osteomyelitis causes refractory infected bone defects characterized by impaired osteogenesis and excessive inflammatory bone destruction. Pyroptosis has emerged as an important driver of infection-related tissue injury, but the upstream regulators in osteoblasts and effective local therapeutic strategies remain poorly defined. This study investigated the role of the MIF-CD74/PI3K/AKT axis in SA-mediated osteoblast dysfunction and evaluated the ISO-1 sustained-release hydrogel for repairing infected bone defects.
Methods:
MIF expression was examined in human osteomyelitis sample. Bone destruction, inflammation, and osteogenesis were compared between wild-type and Mif -/- mice using micro-CT, histology, ELISA, RT-qPCR, and immunohistochemistry. In vitro, SA-infected mouse bone marrow mesenchymal stem cells (mBMSCs) were used to assess proliferation, osteogenic differentiation, and pyroptosis, while MIF and CD74 were silenced with siRNA. RNA sequencing (RNA-seq) and co-immunoprecipitation (Co-IP) were employed to identify MIF downstream receptors and pathways, and PI3K/AKT involvement was verified using CD74 overexpression and the PI3K inhibitor LY294002. An injectable, photocrosslinkable ISO-1@β-CD/GelMA hydrogel was fabricated and characterized for structure, mechanics, and pH-responsive drug release, then implanted into rat femoral infected bone defects after debridement to evaluate bone regeneration and local inflammatory modulation.
Results:
MIF was markedly upregulated in human osteomyelitis and its genetic deletion in mice significantly attenuated SA-induced bone loss, preserved trabecular microarchitecture, enhanced osteogenic marker expression, and reduced local pro-inflammatory cytokines. SA infection suppressed mBMSC proliferation and osteogenic differentiation while activating NLRP3/ASC/GSDMD-dependent pyroptosis. MIF or CD74 knockdown partially restored osteogenesis and decreased inflammatory cytokine release and pyroptotic markers. RNA-seq and Co-IP identified CD74 as a key MIF receptor, with PI3K/AKT as a critical downstream pathway regulating osteoblast fate. The ISO-1@β-CD/GelMA hydrogel showed favorable injectability, mechanical stability, and sustained ISO-1 release, and significantly improved bone volume, microarchitecture, and inflammatory microenvironment in rat infected bone defects.
Conclusion:
SA-induced osteomyelitis disrupts bone homeostasis via the MIF-CD74/PI3K/AKT axis, thereby suppressing osteogenesis and promoting NLRP3/ASC/GSDMD-mediated osteoblast pyroptosis. Targeting MIF with an ISO-1 sustained-release hydrogel remodels the inflammatory and pyroptotic microenvironment, enhances osteogenic differentiation, and effectively promotes repair of infected bone defects, providing a promising translational platform for osteomyelitis-related bone regeneration.
