Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Biochem Biophys Res Commun. 2021 Mar 5;543:87-94. doi: 10.1016/j.bbrc.2021.01.016. Epub 2021 Feb 6.
Age-associated bone loss or osteoporosis is a common clinical manifestation during aging (AG). The mechanism underlying age-associated osteoblast dysfunction induced by oxidative damage in the mitochondria and loss of bone density remains elusive. Here, we demonstrated the effect of allyl sulfide (AS), a natural organosulfur compound, on mitochondrial (mt) function in bone marrow-derived mesenchymal stem cells (BMMSCs) and bone density in AG mice. The data demonstrate that AS treatment in AG mice promotes BMMSCs differentiation and mineralization via inhibition of mitochondrial oxidative damage. The data also indicate that AG related mito-damage was associated with reduced mitochondrial biogenesis and oxidative phosphorylation, and release of a greater concentration of mtDNA. Furthermore, the data showed that mtDNA caused histone H3K27 demethylase inhibition, KDM6B, and subsequent inflammation by unbalancing mitochondrial redox homeostasis. KDM6B overexpression in AG BMMSCs or AS administration in AG mice restores osteogenesis and bone density in vitro and in vivo. Mechanistically, AS or the mitochondrial-specific antioxidant Mito-TEMPO increased KDM6B expression and upregulated the expression of Runx2 in BMMSCs, probably via epigenetic inhibition of H3K27me3 methylation at the promoter. These data uncover the previously undefined role of AS mediated prevention of mtDNA release, promoting osteogenesis and bone density via an epigenetic mechanism. Therefore, AS could be a potential drug target for the treatment of aging-associated osteoporosis.
年龄相关性骨丢失或骨质疏松症是衰老（AG）过程中的一种常见临床表现。线粒体氧化损伤诱导的年龄相关性成骨细胞功能障碍和骨密度丧失的机制仍不清楚。在这里，我们证明了烯丙基硫（AS），一种天然有机硫化合物，对骨髓间充质干细胞（BMMSCs）中线粒体（mt）功能和 AG 小鼠骨密度的影响。数据表明，AS 处理可通过抑制线粒体氧化损伤促进 AG 小鼠的 BMMSCs 分化和矿化。数据还表明，AG 相关的线粒体损伤与线粒体生物发生和氧化磷酸化减少以及更大浓度的 mtDNA 释放有关。此外，数据显示 mtDNA 通过破坏线粒体氧化还原平衡引起组蛋白 H3K27 去甲基化酶抑制、KDM6B，随后引发炎症。AG BMMSCs 中的 KDM6B 过表达或 AG 小鼠中 AS 的给药可恢复体外和体内的成骨作用和骨密度。从机制上讲，AS 或线粒体特异性抗氧化剂 Mito-TEMPO 增加了 BMMSCs 中 KDM6B 的表达并上调了 Runx2 的表达，可能通过组蛋白 H3K27me3 甲基化在启动子处的表观遗传抑制。这些数据揭示了 AS 介导的 mtDNA 释放预防、通过表观遗传机制促进成骨作用和骨密度的先前未定义的作用。因此，AS 可能是治疗与衰老相关的骨质疏松症的潜在药物靶点。
