Oxidative Stress-Induced Osteoblast Dysfunction: Molecular Mechanisms and Protective Effects of Natural Antioxidants

With the global population aging and the increasing prevalence of diabetes, osteoporosis and the aseptic loosening of orthopedic implants have emerged as significant health challenges, with oxidative stress (OS) identified as a central pathological factor mediating osteoblast dysfunction. This thesis systematically investigated the molecular mechanisms and protective strategies concerning OS-induced bone loss in the contexts of osteoporosis, diabetic bone disease, and implant failure. Initially, using an H2O2-induced model, we confirmed the deleterious effects of OS on osteoblast viability and differentiation, revealing the GSK3β-Nrf2 signaling pathway as a crucial endogenous defense mechanism that can be activated by the natural antioxidant curcumin to preserve osteoblastic function. In the context of diabetic pathology, advanced glycation end products (AGEs) were found to induce mitochondrial dysfunction and dynamic imbalance via the RAGE receptor, a process effectively blocked by silibinin to reduce apoptosis. Regarding implant biosafety, this work revealed for the first time that titanium ions trigger apoptosis by inducing CypD-mediated mitochondrial permeability transition pore (mPTP) opening, which was significantly mitigated by the mitochondria-targeted antioxidant MitoQ. To provide a holistic perspective, integrated transcriptomic and proteomic analyses were performed, identifying a core set of seven genes, specifically Ho-1, Fgfr2, and Ccnd2, which constitute a global molecular signature of osteoblast injury under OS. Synthesizing these findings, the thesis proposes that the mitochondrion serves as a "common central hub" for various pathological stimuli leading to bone loss. These results emphasize the potential of multi-target precision therapies focused on mitochondrial protection to improve implant stability and skeletal health, providing a comprehensive theoretical foundation and experimental support for the development of next-generation bone repair materials and personalized pharmacological interventions.