Guo Yuanyuan, Jia Xiong, Cui Yongzhi, Song Yu, Wang Siyuan, Geng Yongtao, Li Rui, Gao Weihang, Fu Dehao
Department of Pharmacy, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Redox Biol. 2021 May;41:101915. doi: 10.1016/j.redox.2021.101915. Epub 2021 Feb 24.
Senile osteoporosis (SOP) is widely regarded as one of the typical aging-related diseases due to a decrease in bone mass and the destruction in microarchitecture. The inhibition of mitophagy can promote bone marrow mesenchymal stem cells (BMSCs) senescence, and increasing studies have shown that interventions targeting BMSCs senescence can ameliorate osteoporosis, exhibiting their potential for use as therapeutic strategies. Sirtuin-3 (Sirt3) is an essential mitochondria metabolic regulatory enzyme that plays an important role in mitochondrial homeostasis, but its role in bone homeostasis remains largely unknown. This study seeks to investigate whether advanced glycation end products (AGEs) accumulation aggravated BMSCs senescence and SOP, and explored the mechanisms underlying these effects. We observed that AGEs significantly aggravated BMSCs senescence, as well as promoted mitochondrial dysfunction and inhibited mitophagy in a concentration-dependent manner. In addition, this effect could be further strengthened by Sirt3 silencing. Importantly, we identified that the reduction of Sirt3 expression and the mitophagy were vital mechanisms in AGEs-induced BMSCs senescence. Furthermore, overexpression of Sirt3 by intravenously injection with recombinant adeno-associated virus 9 carrying Sirt3 plasmids (rAAV-Sirt3) significantly alleviated BMSCs senescence and the formation of SOP in SAMP6. In conclusion, our data demonstrated that Sirt3 protects against AGEs-induced BMSCs senescence and SOP. Targeting Sirt3 to improve mitophagy may represent a potential therapeutic strategy for attenuating AGEs-associated SOP.
老年性骨质疏松症（SOP）因骨量减少和微结构破坏而被广泛认为是典型的衰老相关疾病之一。线粒体自噬的抑制可促进骨髓间充质干细胞（BMSCs）衰老，越来越多的研究表明，针对BMSCs衰老的干预措施可改善骨质疏松症，显示出其作为治疗策略的潜力。沉默调节蛋白3（Sirt3）是一种重要的线粒体代谢调节酶，在维持线粒体稳态中发挥重要作用，但其在骨稳态中的作用仍 largely未知。本研究旨在探讨晚期糖基化终产物（AGEs）的积累是否会加重BMSCs衰老和SOP，并探究其潜在机制。我们观察到，AGEs以浓度依赖的方式显著加重BMSCs衰老，促进线粒体功能障碍并抑制线粒体自噬。此外，Sirt3沉默可进一步增强这种效应。重要的是，我们发现Sirt3表达降低和线粒体自噬是AGEs诱导BMSCs衰老的关键机制。此外，通过静脉注射携带Sirt3质粒的重组腺相关病毒9（rAAV-Sirt3）来过表达Sirt3，可显著减轻SAMP6中BMSCs衰老和SOP的形成。总之，我们的数据表明，Sirt3可保护细胞免受AGEs诱导的BMSCs衰老和SOP。靶向Sirt3以改善线粒体自噬可能是减轻AGEs相关SOP的潜在治疗策略。
