Huang Yu-Sheng, Gao Jia-Wen, Ao Rui-Feng, Liu Xin-Yu, Wu Di-Zheng, Huang Jun-Long, Tu Chen, Zhuang Jing-Shen, Zhu Si-Yuan, Zhong Zhao-Ming
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
J Orthop Translat. 2025 Jan 21;51:24-36. doi: 10.1016/j.jot.2024.12.010. eCollection 2025 Mar.
Skeletal aging is characterized by a decrease in bone mass and an increase in marrowfat content. Advanced oxidation protein products (AOPPs) accumulate easily with aging and disrupt redox homeostasis. We examined whether AOPPs accumulation contributes to the bone-fat imbalance during skeletal aging.
Both young and aged mice were employed to assess the changes of AOPPs levels and its contribution to bone-fat imbalance during skeletal aging. Primary bone marrow mesenchymal stromal cells (MSCs) were used to examine the potential role of AOPPs in age-related switch between osteogenic and adipogenic differentiation. Aged mice were also gavaged by non-selective antioxidant N-acetyl-L-cysteine (NAC), followed by close monitoring of the changes in AOPPs levels and bone-fat metabolism. Furthermore, young mice were chronically exposed to AOPPs and then evaluated for the changes of bone mass and marrow adiposity.
The levels of AOPPs in serum and bone marrow were markedly higher in aged mice than that in young mice. Age-related accumulation of AOPPs was accompanied by reduced bone formation, increased marrow adiposity and deterioration of bone microstructure. Reduced AOPPs accumulation by antioxidant NAC leaded to improvement of the bone-fat imbalance in aged mice. Similarly, the bone-fat imbalance was induced by chronic AOPPs loading in young mice. Compared with MSCs from young mice, MSCs from aged mice tended to differentiate into adipocytes rather than osteoblasts and displayed cellular senescence. Exposure of primary MSCs to AOPPs resulted in the switch from osteogenic to adipogenic lineage and cellular senescence. AOPPs challenge also increased intracellular ROS generation by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. The antioxidant NAC, after scavenging ROS, ameliorated the AOPPs-induced lineage switch and senescence in MSCs by inhibiting the PI3K/AKT/mTOR pathway.
Our findings revealed the involvement of AOPPs in age-related switch between osteogenic and adipogenic differentiation, and illuminated a novel potential mechanism underlying bone-fat imbalance during skeletal aging.
Reducing AOPPs accumulation and its cascading effects on MSCs might be an attractive strategy for delaying skeletal aging.
骨骼老化的特征是骨量减少和骨髓脂肪含量增加。晚期氧化蛋白产物（AOPPs）易随衰老而积累，并破坏氧化还原稳态。我们研究了AOPPs积累是否导致骨骼老化过程中的骨-脂肪失衡。
使用年轻和老年小鼠来评估骨骼老化过程中AOPPs水平的变化及其对骨-脂肪失衡的影响。原代骨髓间充质基质细胞（MSCs）用于研究AOPPs在成骨和成脂分化的年龄相关转变中的潜在作用。对老年小鼠灌胃非选择性抗氧化剂N-乙酰-L-半胱氨酸（NAC），随后密切监测AOPPs水平和骨-脂肪代谢的变化。此外，使年轻小鼠长期暴露于AOPPs，然后评估骨量和骨髓脂肪的变化。
老年小鼠血清和骨髓中的AOPPs水平明显高于年轻小鼠。与年龄相关的AOPPs积累伴随着骨形成减少、骨髓脂肪增多和骨微结构恶化。抗氧化剂NAC减少AOPPs积累可改善老年小鼠的骨-脂肪失衡。同样，年轻小鼠长期暴露于AOPPs会诱导骨-脂肪失衡。与来自年轻小鼠的MSCs相比，来自老年小鼠的MSCs倾向于分化为脂肪细胞而非成骨细胞，并表现出细胞衰老。原代MSCs暴露于AOPPs会导致从成骨谱系向成脂谱系转变以及细胞衰老。AOPPs刺激还通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和线粒体增加细胞内活性氧（ROS）生成。抗氧化剂NAC清除ROS后，通过抑制PI3K/AKT/mTOR途径改善了AOPPs诱导的MSCs谱系转变和衰老。
我们的研究结果揭示了AOPPs参与成骨和成脂分化的年龄相关转变，并阐明了骨骼老化过程中骨-脂肪失衡的一种新的潜在机制。
减少AOPPs积累及其对MSCs的级联效应可能是延缓骨骼老化的一种有吸引力的策略。
