A recent open-access mouse study published by Xi’an Institute of Tissue Engineering and Regenerative Medicine scientists in the journal Bone Research describes how the ALPL gene affects bone aging and suggests that metformin might constitute a viable therapeutic option to prevent it .
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 p16INK4A (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.
ALPL, alkaline phosphatase, and osteoporosis
Alkaline phosphatase is an enzyme encoded by the ALPL gene. The enzyme comes in at least four versions—intestinal, placental, placental-like, and tissue-nonspecific liver/bone/kidney. This enzyme is extremely common in animal life, and it is known to have a role in bone development; it is also used as a diagnostic index to assess the bone-forming capacity in patients suffering from osteoporosis—an age-related condition that weakens bone and increases the risk of fractures—but its role in aging is unclear.
Osteoporosis isn’t accompanied by specific symptoms. Most often, it results in a higher likelihood of falls and breaking a bone, which, in elderly people, can be an extremely serious problem, and fractures may lead to both acute and chronic pain. Bone aging, which leads to bone mass decrease and a simultaneous increase of marrow fat, is the primary risk factor for osteoporosis; it also entails senescence of bone marrow mesenchymal stem cells (MSCs), which are progenitor cells of osteoblasts (bone-synthesizing cells) and adipocytes (fat cells) in the bone marrow. Studies have previously shown that rescuing MSCs significantly improves both bone mass and regenerative capacity, but, again, how ALPL exactly fits into the puzzle remains to be established.
To figure out the role of ALPL in bone aging, the researchers employed ALPL-knockout mouse models; specifically, they employed ALPL+/- knockouts, meaning that only one of the two copies of the gene was inactivated. Compared to the control group (that is, ALPL+/+ mice in which no copy of ALPL was inactive), these knockouts exhibited a 50% drop in the activity of alkaline phosphatase in serum as well as symptoms of bone aging, complete with bone mass loss and marrow fat gain. The scientists observed that the inactivation of ALPL disrupts the balance between osteoblasts and adypocites, pushing MSCs to differentiate more into the latter rather than the former type of cell.
According to the study, ALPL leads to this cell fate change via inhibition of the AMPKα pathway—a central metabolic pathway involved in bone physiology, among other things—which suggested the scientists that metformin, a well-known diabetes drug currently being investigated for its anti-aging potential, might help restore the osteo-adipogenic balance, as it is known to be an AMPKα activator.
Indeed, metformin proved very effective at rescuing MSC differentiation both in cells in vitro and in vivo in the ALPL knockouts; by injecting the drug directly into the knockout mice’s bone marrow, the scientists managed to restore MSC differentiation and prevent bone aging. Apparently, the drug is even more effective than the alternative option of overexpressing the ALPL gene.
The study sheds more light on the role of ALPL and alkaline phosphatase on bone aging, and it does suggest that metformin might be a therapeutic avenue to prevent aging of bone tissue. However, the scientists report that ALPL knockouts displayed the signs of aging in many organs, so future studies may need to further investigate the effects of systematic metformin injections in this knockout model.
 Liu, W., Zhang, L., Xuan, K., Hu, C., Liu, S., Liao, L., … Jin, Y. (2018). Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells. Bone Research, 6(1). doi:10.1038/s41413-018-0029-4