Mutations in the liver/bone/kidney alkaline phosphatase (Alpl) 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 Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16^INK4A (p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells (MSCs). Mechanistically, Alpl 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 Alpl^+/- mice by improving the function of endogenous MSCs. These results identify a previously unknown role of Alpl 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/骨/肾碱性磷酸酶（ Alpl ）基因突变会导致低磷酸酯酶症（HPP）和早发性骨发育不良，表明该基因是人类骨骼发育的关键因素。然而， Alpl在骨骼老化中如何以及在何处发挥作用尚不清楚。在这里，我们确定Alpl的消融会诱导典型的骨过早老化特征，包括骨质流失和骨髓脂肪增加，以及由于间充质干细胞 (MSC) 衰老和分化受损而导致的 p16 ^INK4A (p16) 和 p53 表达升高。从机制上讲，MSC 中Alpl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 MSC 内化，导致细胞内 ATP 水平升高，从而使 AMPKα 通路失活，从而促进 MSC 的细胞命运转换。通过二甲双胍治疗重新激活 AMPKα，可改善内源性 MSC 的功能，成功预防Alpl ^+/-小鼠的骨过早老化。这些结果确定了Alpl在调节 ATP 介导的 AMPKα 改变中的先前未知的作用，从而维持 MSC 干细胞性并防止骨老化，并表明二甲双胍提供了潜在的治疗选择。