Ali Md Mohsin, Nookaew Intawat, Resende-Coelho Ana, Marques-Carvalho Adriana, Warren Aaron, Fu Qiang, Kim Ha-Neui, O'Brien Charles A, Almeida Maria
Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Biol Chem. 2025 Jul 31;301(9):110551. doi: 10.1016/j.jbc.2025.110551.
Mitochondrial reactive oxygen species (ROS), insufficient NAD, and cellular senescence all contribute to the decrease in bone formation with aging. ROS can cause senescence and decrease NAD, but it remains unknown whether these mechanisms mediate the effects of ROS in vivo. Here, we generated mice with deletion of the mitochondrial antioxidant enzyme Sod2 in Osx1-Cre (Sp7-tTA,tetO-EGFP/cre) targeted cells, designated Sod2. We showed that Sod2 deletion caused low bone mass. Osteoblastic cells from these mice had impaired mitochondrial respiration and attenuated NAD levels. Administration of an NAD precursor improved mitochondrial function in vitro but failed to rescue the low bone mass of Sod2 mice. Single-cell RNA-sequencing of bone mesenchymal cells indicated that ROS had no significant effects on markers of senescence but disrupted parathyroid hormone signaling, iron metabolism, and proteostasis. Our data support the rationale that treatment combinations aimed at decreasing mitochondrial ROS and senescent cells and increasing NAD should confer additive effects in delaying age-associated osteoporosis.
线粒体活性氧（ROS）、NAD不足和细胞衰老都导致随着年龄增长骨形成减少。ROS可导致衰老并降低NAD，但这些机制是否介导ROS在体内的作用仍不清楚。在此，我们构建了在Osx1-Cre（Sp7-tTA，tetO-EGFP/cre）靶向细胞中缺失线粒体抗氧化酶Sod2的小鼠，命名为Sod2。我们发现Sod2缺失导致骨量降低。这些小鼠的成骨细胞线粒体呼吸受损，NAD水平降低。给予NAD前体可改善体外线粒体功能，但未能挽救Sod2小鼠的低骨量。骨间充质细胞的单细胞RNA测序表明，ROS对衰老标志物没有显著影响，但会破坏甲状旁腺激素信号、铁代谢和蛋白质稳态。我们的数据支持这样的理论基础，即旨在减少线粒体ROS和衰老细胞并增加NAD的联合治疗应在延缓年龄相关性骨质疏松症方面具有累加效应。
