Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Osteogenic Differentiation by Modulating AMPK/ULK1‐Dependent Autophagy

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a rate‐limiting enzyme that plays critical roles in multiple physiological processes. The decompensation of PCK2 leads to various energy metabolic disorders. However, little is known regarding the effects of PCK2 on osteogenesis by human mese...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2019-12, Vol.37 (12), p.1542-1555
Main Authors: Li, Zheng, Liu, Xuenan, Zhu, Yuan, Du, Yangge, Liu, Xuejiao, Lv, Longwei, Zhang, Xiao, Liu, Yunsong, Zhang, Ping, Zhou, Yongsheng
Format: Article
Language:English
Subjects:
AMP
Autophagy
Biomedical materials
Bone diseases
Bone growth
Differentiation (biology)
Kinases
Mesenchymal stem cells
Mesenchyme
Metabolic disorders
Metabolism
Mitochondria
Mitochondrial phosphoenolpyruvate carboxykinase
Osteogenesis
Osteogenic differentiation
Phagocytosis
Protein kinase
Stem Cell Technology: Epigenetics, Genomics, Proteomics, and Metabonomics
Stem cells
Tissue engineering
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Summary:Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a rate‐limiting enzyme that plays critical roles in multiple physiological processes. The decompensation of PCK2 leads to various energy metabolic disorders. However, little is known regarding the effects of PCK2 on osteogenesis by human mesenchymal stem cells (hMSCs). Here, we report a novel function of PCK2 as a positive regulator of MSCs osteogenic differentiation. In addition to its well‐known role in anabolism, we demonstrate that PCK2 regulates autophagy. PCK2 deficiency significantly suppressed autophagy, leading to the impairment of osteogenic capacity of MSCs. On the other hand, autophagy was promoted by PCK2 overexpression; this was accompanied by increased osteogenic differentiation of MSCs. Moreover, PCK2 regulated osteogenic differentiation of MSCs via AMP‐activated protein kinase (AMPK)/unc‐51 like autophagy activating kinase 1(ULK1)‐dependent autophagy. Collectively, our present study unveiled a novel role for PCK2 in integrating autophagy and bone formation, providing a potential target for stem cell‐based bone tissue engineering that may lead to improved therapies for metabolic bone diseases. Stem Cells 2019;37:1542–1555 The essential role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in regulating gluconeogenesis and TCA cycle flux makes it indispensable for mesenchymal stem cells osteogenic differentiation, which is a nutrient‐consuming process. PCK2 regulates osteogenic differentiation of mesenchymal stem cells through modulating autophagy. The phosphorylation of AMP‐activated protein kinase (AMPK) and phosphorylation unc‐51 like autophagy activating kinase 1 (ULK1) are regulated by PCK2 during osteogenic differentiation, suggesting that AMPK/ULK1‐mediated autophagy is involved in the PCK2 regulated osteogenic capacity of mesenchymal stem cells.
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.3091