Liu Wenjia, Zhang Liqiang, Xuan Kun, Hu Chenghu, Liu Shiyu, Liao Li, Li Bei, Jin Fang, Shi Songtao, Jin Yan
1MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, China.
Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.
Bone Res. 2018 Sep 11;6:27. doi: 10.1038/s41413-018-0029-4. eCollection 2018.
Mutations in the liver/bone/kidney alkaline phosphatase () gene cause hypophosphatasia (HPP) and early-onset bone dysplasia, suggesting that this gene is a key factor in human bone development. However, how and where acts in bone ageing is largely unknown. Here, we determined that ablation of induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16 (p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells (MSCs). Mechanistically, deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in mice by improving the function of endogenous MSCs. These results identify a previously unknown role of in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.
肝脏/骨骼/肾脏碱性磷酸酶（）基因突变会导致低磷血症（HPP）和早发性骨发育异常，这表明该基因是人类骨骼发育的关键因素。然而，在骨骼衰老过程中如何发挥作用以及作用部位在很大程度上尚不清楚。在这里，我们确定敲除会诱发典型的过早骨骼衰老特征，包括骨量减少和骨髓脂肪增加，同时由于间充质干细胞（MSCs）衰老和分化受损，导致p16（p16）和p53表达升高。从机制上讲，MSCs中的缺乏会增强ATP释放并减少ATP水解。然后，过量的细胞外ATP反过来被MSCs内化，导致细胞内ATP水平升高，从而使AMPKα途径失活，并导致MSCs的细胞命运转变。通过二甲双胍治疗重新激活AMPKα可通过改善内源性MSCs的功能成功预防小鼠过早骨骼衰老。这些结果确定了在调节ATP介导的AMPKα改变中的一个以前未知的作用，这种改变维持了MSCs的干性并防止骨骼衰老，并表明二甲双胍提供了一种潜在的治疗选择。
