FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus.
FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus.
复制标题
FFA-ROS-P53介导的线粒体凋亡有助于减少2型糖尿病中的成骨细胞生成和骨量
DOI：
10.1038/srep12724
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发表时间：
2015-07-31
影响因子：
4.6
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Li J;He W;Liao B;Yang J
本研究评价2型糖尿病患者游离脂肪酸（FFA）、活性氧（ROS）生成、线粒体功能障碍与骨密度（BMD）的关系，并探讨其分子机制。db/db和高脂（HF）喂养的小鼠接受Etomoxir（CPT 1抑制剂）、MitoQ和PFT-α（P53抑制剂）治疗。评估骨代谢因素，分离骨髓间充质干细胞并诱导成骨分化。FFA、脂质过氧化、mtDNA拷贝数与T2 DM患者BMD相关。Etomoxir、MitoQ和PFT-α可显著抑制db/db和HF喂养小鼠BMD和骨断裂强度的下降，并抑制BMSCs分化成骨细胞的减少。Etomoxir和MitoQ，而不是PFT-α，抑制db/db和HF喂养的小鼠和成骨细胞中线粒体ROS生成的增加。此外，Etomoxir、MitoQ和PFT-α显著抑制成骨细胞中的线粒体功能障碍。此外，db/db和HF喂养小鼠来源的成骨细胞中的线粒体凋亡被激活，Etomoxir、MitoQ和PFT-α可抑制线粒体凋亡。此外，线粒体积累的P53招募Bax和启动凋亡事件的分子事件。这些结果表明，脂肪酸氧化导致ROS产生，激活P53/P53介导的线粒体凋亡，导致T2 DM成骨分化减少和骨丢失。
This study evaluated the association between free fatty acid (FFA), ROS generation, mitochondrial dysfunction and bone mineral density (BMD) in type 2 diabetic patients and investigated the molecular mechanism. db/db and high fat (HF)-fed mice were treated by Etomoxir, an inhibitor of CPT1, MitoQ and PFT-α, an inhibitor of P53. Bone metabolic factors were assessed and BMSCs were isolated and induced to osteogenic differentiation. FFA, lipid peroxidation and mtDNA copy number were correlated with BMD in T2DM patients. Etomoxir, MitoQ and PFT-α significantly inhibited the decrease of BMD and bone breaking strength in db/db and HF-fed mice and suppressed the reduction of BMSCs-differentiated osteoblasts. Etomoxir and MitoQ, but not PFT-α, inhibited the increase of mitochondrial ROS generation in db/db and HF-fed mice and osteoblasts. In addition, Etomoxir, MitoQ and PFT-α significantly inhibited mitochondrial dysfunction in osteoblasts. Moreover, mitochondrial apoptosis was activated in osteoblasts derived from db/db and HF-fed mice, which was inhibited by Etomoxir, MitoQ and PFT-α. Furthermore, mitochondrial accumulation of P53 recruited Bax and initiated molecular events of apoptotic events. These results demonstrated that fatty acid oxidation resulted in ROS generation, activating P53/Bax-mediated mitochondrial apoptosis, leading to reduction of osteogenic differentiation and bone loss in T2DM.