prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells.

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.