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

Abstract

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.

Cell biology: diabetes drug prevents bone aging

The diabetes drug metformin restores the ability of stem cells to grow and differentiate into bone-producing osteoblasts, preventing bone aging. The alkaline phosphatase gene (Alpl) has been implicated in abnormal bone and tooth development, but its role in bone aging was unclear. The protein it encodes is enriched in the cell membrane of mesenchymal stem cells (MSCs) – precursors of bone-producing osteoblasts – and is involved in the metabolism of ATP, which is implicated in MSC differentiation. Here, Yan Lin at the Xi’an Institute of Tissue Engineering and Regenerative Medicine in China and colleagues demonstrate that Alpl deficiency contributes to bone aging by boosting levels of extracellular ATP. When internalized, this triggers the AMPKα pathway and impairs MSCs’ ability to grow and differentiate. Treatment with metformin reactivates this pathway and prevents premature bone aging.

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Funding

his work was financially supported through grants from the Nature Science Foundation of China (81620108007), the National key Research and Development Program of China (2016YFC1101400), Nature Science Foundation of China (31571532, 31601099) and National Institutes of Health, Department of Health and Human Services (R01DE017449 to S.S.).