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

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 AMPKa pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKa 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 AMPKa alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.