Liu Yao, Kou Xiaoxing, Chen Chider, Yu Wenjing, Su Yingying, Kim Yong, Shi Songtao, Liu Yi
Department of Pediatric Dentistry, School of Stomatology, China Medical University, Shenyang, China.
Liaoning Province Key Laboratory of Oral Disease, Shenyang, China.
Stem Cells. 2016 Aug;34(8):2157-68. doi: 10.1002/stem.2392. Epub 2016 May 30.
Chronic consumption of excessive alcohol results in reduced bone mass, impaired bone structure, and increased risk of bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are not fully understood. Here, we show that high dose chronic alcohol consumption reduces osteogenic differentiation and enhances adipogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), leading to osteopenia in a mouse model. Mechanistically, impaired osteo/adipogenic lineage differentiation of BMMSCs is due to activation of a phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (mTOR) signaling cascade, resulting in downregulation of runt-related transcription factor 2 and upregulation of peroxisome proliferator-activated receptor gamma via activation of p70 ribosomal protein S6 kinase. Blockage of the mTOR pathway by rapamycin treatment ameliorates alcohol-induced osteopenia by rescuing impaired osteo/adipogenic lineage differentiation of BMMSCs. In this study, we identify a previously unknown mechanism by which alcohol impairs BMMSC lineage differentiation and reveal a potential rapamycin-based drug therapy for alcohol-induced osteoporosis. Stem Cells 2016;34:2157-2168.
长期过量饮酒会导致骨量减少、骨结构受损以及骨折风险增加。然而，酒精性骨质疏松症的潜在机制尚未完全明确。在此，我们表明，高剂量长期饮酒会降低骨髓间充质干细胞（BMMSC）的成骨分化并增强其成脂分化，从而在小鼠模型中导致骨质减少。从机制上来说，BMMSC的成骨/成脂谱系分化受损是由于磷脂酰肌醇3激酶/蛋白激酶B/雷帕霉素哺乳动物靶蛋白（mTOR）信号级联的激活，通过激活p70核糖体蛋白S6激酶导致与矮小相关转录因子2的下调以及过氧化物酶体增殖物激活受体γ的上调。用雷帕霉素治疗阻断mTOR通路可通过挽救BMMSC受损的成骨/成脂谱系分化来改善酒精性骨质减少。在本研究中，我们确定了一种酒精损害BMMSC谱系分化的前所未知的机制，并揭示了一种基于雷帕霉素的酒精性骨质疏松症潜在药物治疗方法。《干细胞》2016年；34卷：2157-2168页
