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      PKM2 suppresses osteogenesis and facilitates adipogenesis by regulating β-catenin signaling and mitochondrial fusion and fission

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          Abstract

          Bone marrow mesenchymal stem cells (BMSCs) differentiation dysfunction is a common pathological phenotype of several prevalent metabolic and genetic bone diseases. Pyruvate kinase muscle isoenzyme 2 (PKM2) regulates the last step of glycolysis, and its role in BMSCs differentiation is still unknown. In this study, the influence of PKM2 on osteogenesis and adipogenesis was assessed in vitro and in vivo. We found that DASA-58 (the activator of PKM2) reduced the enzymatic activity of ALP, and inhibited the levels of osteogenic marker genes, especially RUNX2, which is a crucial transcription factor for osteogenesis. Besides, we provided evidence that C3k, an inhibitor of PKM2, caused increase in mitochondrial membrane potential and maintained low levels of ROS, and promoted mitochondrial fusion. Furthermore, after treatment with DASA-58, the level of active β-catenin gradually decreased, which also inhibited the transport of active β-catenin into the nucleus, but C3k obviously promoted its nuclear translocation. As for adipogenesis, PKM2 activation increased the expression of adipogenic related genes and decreased active-β-catenin expression, whereas treatment of C3k had the opposite effect. In addition, C3k significantly attenuated ovariectomy-induced trabecular bone loss in vivo. Our findings helped uncover the molecular mechanisms underlying PKM2 regulation of BMSCs differentiation.

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          Most cited references32

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          Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

          Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
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            PKM2 contributes to cancer metabolism.

            Reprogramming of cell metabolism is essential for tumorigenesis, and is regulated by a complex network, in which PKM2 plays a critical role. PKM2 exists as an inactive monomer, less active dimer and active tetramer. While dimeric PKM2 diverts glucose metabolism towards anabolism through aerobic glycolysis, tetrameric PKM2 promotes the flux of glucose-derived carbons for ATP production via oxidative phosphorylation. Equilibrium of the PKM2 dimers and tetramers is critical for tumorigenesis, and is controlled by multiple factors. The PKM2 dimer also promotes aerobic glycolysis by modulating transcriptional regulation. We will discuss the current understanding of PKM2 in regulating cancer metabolism.
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              Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

              In mammals, Wnt/β-catenin signaling features prominently in stem cells and cancers, but how and for what purposes have been matters of debate. In this review, Lien and Fuchs summarize the current knowledge of Wnt/β-catenin signaling and its downstream transcriptional regulators in normal and malignant stem cells, with particular emphasis on embryonic stem cells, hair follicle stem cells, and intestinal epithelial stem cells.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                29 February 2020
                25 February 2020
                : 12
                : 4
                : 3976-3992
                Affiliations
                [1 ]Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                [2 ]Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Jun Xiao; email: jun_xiao@hust.edu.cn
                Correspondence to: Tao Xu; email: xutao0101@yeah.net
                Article
                102866 102866
                10.18632/aging.102866
                7066892
                32096765
                56ad44c4-604a-4669-a364-a719048dba39
                Copyright © 2020 Guo et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 October 2019
                : 04 February 2020
                Categories
                Research Paper

                Cell biology
                pkm2,osteogenesis,adipogenesis,mitochondrial fusion and fission,β-catenin signaling
                Cell biology
                pkm2, osteogenesis, adipogenesis, mitochondrial fusion and fission, β-catenin signaling

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