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

Abstract

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

Mitochondrial Phosphoenolpyruvate Carboxykinase (PCK2) Maintains the Function of Bone Marrow Mesenchymal Stromal/stem Cells to Rescue Osteoporotic Phenotype Partly Through Autophagy Dependent Manner

“…These factors containing of age and the estrogen depletion would bring changes to the microenvironment of the bone marrow cavity, which can lead to increase of adipose formation and inhibition of bone formation [31]. We observed that PCK2 could promote osteogenic differentiation of MSCs previously [18] and indicated that PCK2 could suppress the adipogenic differentiation of MSCs in this study, so we further determined the effect of lentivirus-mediated PCK2 overexpression on osteoporosis of mice caused by OVX and aging. Our previous work showed that PCK2 regulates osteogenic differentiation of MSCs through AMPK/ULK1-dependent autophagy [18], giving us the clue to explore the role of autophagy in the regulation of PCK2 reversing the bone loss of osteoporotic mice.…”

“…Autophagy is a conserved physical process which is essential for cell survival, differentiation, development, and homeostasis [33]. Our previous study suggested that PCK2 regulates osteogenic differentiation of MSCs through modulating autophagy [18]. We further investigated whether PCK2 could rescue the regenerative capability of endogenous BMMSCs in OVX and aged mice through autophagy.…”

“…Our previous work revealed that PCK2 is a positive regulator in osteogenic differentiation of MSCs [18].…”

“…To further explore the role of PCK2 in regulating adipogenesis, we next constructed stable PCK2 knockdown or overexpression cells and the lentivirus transfection e ciency was evaluated, as described in our previous article [18]. Oil Red O staining and quanti cation showed that the number of lipid droplets grew in PCK2-knockdown group (Fig.…”

The mTOR/ULK1 signaling pathway mediates the autophagy-promoting and osteogenic effects of dicalcium silicate nanoparticles

“…Studies have also shown that AMPK may induce autophagy by directly activating ULK1 or inhibiting mTOR [ 15 ]. Activation of the AMPK/ULK1-dependent autophagy can be correlated positively with osteogenic differentiation of MSCs [ 20 , 21 ], and ULK1 overexpression or rapamycin can activate autophagy and then notably elevate the osteoblast differentiation activity and restore the bone volume [ 22 ].…”