Yang Xiao, Cao Xiankun, Wang Xin, Guo Jiadong, Yang Yangzi, Lu Liqiang, Zhang Pu, Yang Huan, Rong Kewei, Zhou Tangjun, Hao Yongqiang, Zhao Jie, Fu Jingke, Zhang Kai
Shanghai Key Laboratory of Orthopedic Implants Department of Orthopedics Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China.
Department of Orthopedic Surgery Spine Center Changzheng Hospital Navy Medical University Shanghai China.
Exploration (Beijing). 2025 Jan 17;5(2):20230174. doi: 10.1002/EXP.20230174. eCollection 2025 Apr.
Intervertebral disc degeneration (IVDD) is a chronic musculoskeletal disorder causing lower back pain, imposing a considerable burden on global health. Hyperglycemia resulting from diabetes mellitus induces advanced glycation end products (AGEs) accumulation in nucleus pulposus cells, leading to IVDD. Mitigating AGEs accumulation is a novel promising strategy for IVDD management. In our study, palladium nanoparticles (Pd NPs) preferentially colocalized within the endoplasmic reticulum and efficiently degraded AGEs via valosin-containing protein (VCP)-mediated autophagy pathways. Pd NPs promoted the ATPase activity of VCPs, upregulated microtubule-associated proteins 1A/1B light chain 3 (LC3) expression, and increased AGEs-degrading autophagosome production. They ameliorated mitochondrial function, relieved endoplasmic reticulum stress, and counteracted the detrimental oxidative stress microenvironment in a high-glucose/high-fat-induced nucleus pulposus cell degeneration model. Consequently, Pd NPs effectively rescued nucleus pulposus cell degeneration in vitro, restored disc height and partially recovered the degenerated phenotype of IVDD in vivo. We provide novel insights regarding IVDD management by targeting AGEs degradation, showing potential for clinical practice.
椎间盘退变（IVDD）是一种慢性肌肉骨骼疾病，可导致下背部疼痛，给全球健康带来相当大的负担。糖尿病引起的高血糖会诱导晚期糖基化终产物（AGEs）在髓核细胞中积累，从而导致IVDD。减轻AGEs的积累是一种治疗IVDD的新的有前景的策略。在我们的研究中，钯纳米颗粒（Pd NPs）优先在内质网中共同定位，并通过含缬酪肽蛋白（VCP）介导的自噬途径有效降解AGEs。Pd NPs促进了VCP的ATP酶活性，上调了微管相关蛋白1A/1B轻链3（LC3）的表达，并增加了降解AGEs的自噬体的产生。在高糖/高脂诱导的髓核细胞退变模型中，它们改善了线粒体功能，减轻了内质网应激，并对抗了有害的氧化应激微环境。因此，Pd NPs在体外有效挽救了髓核细胞退变，在体内恢复了椎间盘高度并部分恢复了IVDD的退变表型。我们通过靶向AGEs降解为IVDD的治疗提供了新的见解，显示出在临床实践中的潜力。
