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...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.展开更多
Spatial regulation of microtubule catastrophe is important for controlling microtubule length and consequently contributes to the proper establishment of cell polarity and cell growth.The+TIP proteins including Tipl/C...Spatial regulation of microtubule catastrophe is important for controlling microtubule length and consequently contributes to the proper establishment of cell polarity and cell growth.The+TIP proteins including Tipl/CLIP-170,Klp5/Kinesin-8,and Alpl4/XMAP215 reside at microtubule plus ends to regulate microtubule dynamics.In the fission yeast Schizosaccharomyces pombe,Tipi and Alpl4 serve as microtubule-stabilizing factors,while Klp5 functions oppositely as a catastrophe-promoting factor.Despite that Tipi has been shown to play a key role in restricting microtubule catastrophe to the cell end,how Tipi fulfills the role remains to be determined.Employing live-cell microscopy,we showed that the absence of Tip i impairs the localization of both Klp5 and Alpl4 at microtubule plus ends,but the absence of Klp5 prolongs the residence time of Tipi at microtubule plus ends.We further revealed that Klp5 accumulates behind Tip i at microtubule plus ends in a Tipl-dependent manner.In addition,artificially tethering Klp5 to microtubule plus ends promotes premature microtubule catastrophe,while tethering Alpl4 to microtubule plus ends in the cells lacking Tipi rescues the phenotype of short microtubules.These findings establish that Tipi restricts microtubule catastrophe to the cell end likely by spatially restricting the microtubule catastrophe activity of Klp5 and stabilizing Alpl4 at microtubule plus ends.Thus,the work demonstrates the orchestration of Tipi,Alpl4,and Klp5 in ensuring microtubule catastrophe at the cell end.展开更多
基金financially supported by grants from the Nature Science Foundation of China (81620108007)National Key Research and Development Program of China (2016YFC1101400)+1 种基金Nature Science Foundation of China (31571532, 31601099)National Institutes of Health, Department of Health and Human Services (R01DE017449 to S.S.)
文摘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.
基金the National Key Research and Development Program of China(2018YFC1004700)the National Natural Science Foundation of China(91754106,31671406,31871350,and 31601095)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB190A0101)the Major/lnnovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2017FXCX008)China’s 1000 Young Talents Recruitment Program.
文摘Spatial regulation of microtubule catastrophe is important for controlling microtubule length and consequently contributes to the proper establishment of cell polarity and cell growth.The+TIP proteins including Tipl/CLIP-170,Klp5/Kinesin-8,and Alpl4/XMAP215 reside at microtubule plus ends to regulate microtubule dynamics.In the fission yeast Schizosaccharomyces pombe,Tipi and Alpl4 serve as microtubule-stabilizing factors,while Klp5 functions oppositely as a catastrophe-promoting factor.Despite that Tipi has been shown to play a key role in restricting microtubule catastrophe to the cell end,how Tipi fulfills the role remains to be determined.Employing live-cell microscopy,we showed that the absence of Tip i impairs the localization of both Klp5 and Alpl4 at microtubule plus ends,but the absence of Klp5 prolongs the residence time of Tipi at microtubule plus ends.We further revealed that Klp5 accumulates behind Tip i at microtubule plus ends in a Tipl-dependent manner.In addition,artificially tethering Klp5 to microtubule plus ends promotes premature microtubule catastrophe,while tethering Alpl4 to microtubule plus ends in the cells lacking Tipi rescues the phenotype of short microtubules.These findings establish that Tipi restricts microtubule catastrophe to the cell end likely by spatially restricting the microtubule catastrophe activity of Klp5 and stabilizing Alpl4 at microtubule plus ends.Thus,the work demonstrates the orchestration of Tipi,Alpl4,and Klp5 in ensuring microtubule catastrophe at the cell end.
