Skip to main content
Top
Published in: BMC Musculoskeletal Disorders 1/2022

Open Access 01-12-2022 | Research

Nutritional deficiency induces nucleus pulposus cell apoptosis via the ATF4-PKM2-AKT signal axis

Authors: Ningfeng Zhou, Bin Shen, Chong Bai, Liang Ma, Shanjin Wang, Desheng Wu

Published in: BMC Musculoskeletal Disorders | Issue 1/2022

Login to get access

Abstract

Background

The intervertebral disc is the largest avascular tissue in the human body. The nucleus pulposus (NP) consumes glucose and oxygen to generate energy to maintain cellular metabolism via nutrients that diffuse from the cartilage endplate. The microenvironment in the intervertebral disc becomes nutritionally deficient during degeneration, and nutritional deficiency has been shown to inhibit the viability and proliferation of NP cells.

Methods

To investigate the molecular mechanism by which nutritional deficiency reduces viability and decreases proliferation, we created an in vitro model by using decreasing serum concentration percentages.

Results

In this study, we found that nutritional deficiency reduced NP cell viability and increased cell apoptosis and that the upregulation of ATF4 expression and the downregulation of PKM2 expression were involved in this process. Moreover, we found that PKM2 inhibition can reduce the cell apoptosis induced by ATF4 silence under nutritional deficiency.

Conclusion

Our findings revealed that PKM2 inhibition reduces the cell apoptosis induced by ATF4 silence under nutritional deficiency by inhibiting AKT phosphate. Revealing the function and mechanism of NP cell development under nutritional deficiency will provide new insights into the etiology, diagnosis, and treatment of intervertebral disc and related diseases.
Appendix
Available only for authorised users
Literature
1.
go back to reference Moriguchi Y, Alimi M, Khair T, Manolarakis G, Berlin C, Bonassar LJ, Hartl R. Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of In Vivo Animal and Clinical Data. Global Spine J. 2016;6(5):497–518.PubMedPubMedCentralCrossRef Moriguchi Y, Alimi M, Khair T, Manolarakis G, Berlin C, Bonassar LJ, Hartl R. Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of In Vivo Animal and Clinical Data. Global Spine J. 2016;6(5):497–518.PubMedPubMedCentralCrossRef
2.
go back to reference Chen F, Wu T, Bai C, Guo S, Huang W, Pan Y, Zhang H, Wu D, Fu Q, Chen Q, et al. Serum apolipoprotein B/apolipoprotein A1 ratio in relation to intervertebral disk herniation: a cross-sectional frequency-matched case-control study. Lipids Health Dis. 2021;20(1):79.PubMedPubMedCentralCrossRef Chen F, Wu T, Bai C, Guo S, Huang W, Pan Y, Zhang H, Wu D, Fu Q, Chen Q, et al. Serum apolipoprotein B/apolipoprotein A1 ratio in relation to intervertebral disk herniation: a cross-sectional frequency-matched case-control study. Lipids Health Dis. 2021;20(1):79.PubMedPubMedCentralCrossRef
3.
go back to reference Miller JA, Schmatz C, Schultz AB. Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976). 1988;13(2):173–8.CrossRef Miller JA, Schmatz C, Schultz AB. Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976). 1988;13(2):173–8.CrossRef
4.
go back to reference Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976). 2006;31(18):2151–61.CrossRef Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976). 2006;31(18):2151–61.CrossRef
5.
go back to reference Vincent K, Mohanty S, Pinelli R, Bonavita R, Pricop P, Albert TJ, Dahia CL. Aging of mouse intervertebral disc and association with back pain. Bone. 2019;123:246–59.PubMedPubMedCentralCrossRef Vincent K, Mohanty S, Pinelli R, Bonavita R, Pricop P, Albert TJ, Dahia CL. Aging of mouse intervertebral disc and association with back pain. Bone. 2019;123:246–59.PubMedPubMedCentralCrossRef
6.
go back to reference Li X, Han Y, Cui J, Yuan P, Di Z, Li L: Efficacy of Warm Needle Moxibustion on Lumbar Disc Herniation: A Meta-Analysis. Journal of evidence-based complementary & alternative medicine 2016, 21(4):311–319. Li X, Han Y, Cui J, Yuan P, Di Z, Li L: Efficacy of Warm Needle Moxibustion on Lumbar Disc Herniation: A Meta-Analysis. Journal of evidence-based complementary & alternative medicine 2016, 21(4):311–319.
7.
go back to reference Li X, Han Y, Di Z, Cui J, Pan J, Yang M, Sun G, Tan J, Li L. Percutaneous endoscopic lumbar discectomy for lumbar disc herniation. J Clin Neurosci. 2016;33:19–27.PubMedCrossRef Li X, Han Y, Di Z, Cui J, Pan J, Yang M, Sun G, Tan J, Li L. Percutaneous endoscopic lumbar discectomy for lumbar disc herniation. J Clin Neurosci. 2016;33:19–27.PubMedCrossRef
8.
go back to reference Li X, Hu Z, Cui J, Han Y, Pan J, Yang M, Tan J, Sun G, Li L. Percutaneous endoscopic lumbar discectomy for recurrent lumbar disc herniation. Int J Surg. 2016;27:8–16.PubMedCrossRef Li X, Hu Z, Cui J, Han Y, Pan J, Yang M, Tan J, Sun G, Li L. Percutaneous endoscopic lumbar discectomy for recurrent lumbar disc herniation. Int J Surg. 2016;27:8–16.PubMedCrossRef
9.
go back to reference Smith LJ, Chiaro JA, Nerurkar NL, Cortes DH, Horava SD, Hebela NM, Mauck RL, Dodge GR, Elliott DM. Nucleus pulposus cells synthesize a functional extracellular matrix and respond to inflammatory cytokine challenge following long-term agarose culture. Eur Cell Mater. 2011;22:291–301.PubMedPubMedCentralCrossRef Smith LJ, Chiaro JA, Nerurkar NL, Cortes DH, Horava SD, Hebela NM, Mauck RL, Dodge GR, Elliott DM. Nucleus pulposus cells synthesize a functional extracellular matrix and respond to inflammatory cytokine challenge following long-term agarose culture. Eur Cell Mater. 2011;22:291–301.PubMedPubMedCentralCrossRef
10.
go back to reference Zheng L, Cao Y, Ni S, Qi H, Ling Z, Xu X, Zou X, Wu T, Deng R, Hu B, et al. Ciliary parathyroid hormone signaling activates transforming growth factor-beta to maintain intervertebral disc homeostasis during aging. Bone Res. 2018;6:21.PubMedPubMedCentralCrossRef Zheng L, Cao Y, Ni S, Qi H, Ling Z, Xu X, Zou X, Wu T, Deng R, Hu B, et al. Ciliary parathyroid hormone signaling activates transforming growth factor-beta to maintain intervertebral disc homeostasis during aging. Bone Res. 2018;6:21.PubMedPubMedCentralCrossRef
11.
go back to reference Hickman TT, Rathan-Kumar S, Peck SH. Development, Pathogenesis, and Regeneration of the Intervertebral Disc: Current and Future Insights Spanning Traditional to Omics Methods. Front Cell Dev Biol. 2022;10:841831.PubMedPubMedCentralCrossRef Hickman TT, Rathan-Kumar S, Peck SH. Development, Pathogenesis, and Regeneration of the Intervertebral Disc: Current and Future Insights Spanning Traditional to Omics Methods. Front Cell Dev Biol. 2022;10:841831.PubMedPubMedCentralCrossRef
12.
go back to reference Li X, Yang S, Qin L, Yang S. Type II collagen-positive embryonic progenitors are the major contributors to spine and intervertebral disc development and repair. Stem Cells Transl Med. 2021;10(10):1419–32.PubMedPubMedCentralCrossRef Li X, Yang S, Qin L, Yang S. Type II collagen-positive embryonic progenitors are the major contributors to spine and intervertebral disc development and repair. Stem Cells Transl Med. 2021;10(10):1419–32.PubMedPubMedCentralCrossRef
13.
go back to reference Li X, Yang S, Yuan G, Jing D, Qin L, Zhao H, Yang S. Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation. Bone Res. 2022;10(1):46.PubMedPubMedCentralCrossRef Li X, Yang S, Yuan G, Jing D, Qin L, Zhao H, Yang S. Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation. Bone Res. 2022;10(1):46.PubMedPubMedCentralCrossRef
14.
go back to reference Ohnishi T, Iwasaki N, Sudo H. Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review. Cells 2022, 11(3). Ohnishi T, Iwasaki N, Sudo H. Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review. Cells 2022, 11(3).
15.
go back to reference Zhang C, Peng X, Wang F, Xie Z, Chen L, Wu X. Update on the Correlation Between Mitochondrial Dysfunction and Intervertebral Disk Degeneration. DNA Cell Biol. 2022;41(3):257–61.PubMedCrossRef Zhang C, Peng X, Wang F, Xie Z, Chen L, Wu X. Update on the Correlation Between Mitochondrial Dysfunction and Intervertebral Disk Degeneration. DNA Cell Biol. 2022;41(3):257–61.PubMedCrossRef
16.
go back to reference Han Y, Li X, Yan M, Yang M, Wang S, Pan J, Li L, Tan J. Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration. Biochem Biophys Res Commun. 2019;516(3):1026–32.PubMedCrossRef Han Y, Li X, Yan M, Yang M, Wang S, Pan J, Li L, Tan J. Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration. Biochem Biophys Res Commun. 2019;516(3):1026–32.PubMedCrossRef
17.
go back to reference Holm S, Maroudas A, Urban JP, Selstam G, Nachemson A. Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res. 1981;8(2):101–19.PubMedCrossRef Holm S, Maroudas A, Urban JP, Selstam G, Nachemson A. Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res. 1981;8(2):101–19.PubMedCrossRef
18.
go back to reference Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine. 2001;26(23):2543–9.PubMedCrossRef Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine. 2001;26(23):2543–9.PubMedCrossRef
19.
go back to reference Bibby SR, Jones DA, Ripley RM, Urban JP. Metabolism of the intervertebral disc: effects of low levels of oxygen, glucose, and pH on rates of energy metabolism of bovine nucleus pulposus cells. Spine. 2005;30(5):487–96.PubMedCrossRef Bibby SR, Jones DA, Ripley RM, Urban JP. Metabolism of the intervertebral disc: effects of low levels of oxygen, glucose, and pH on rates of energy metabolism of bovine nucleus pulposus cells. Spine. 2005;30(5):487–96.PubMedCrossRef
20.
21.
go back to reference Dolor A, Sampson SL, Lazar AA, Lotz JC, Szoka FC, Fields AJ. Matrix modification for enhancing the transport properties of the human cartilage endplate to improve disc nutrition. PLoS ONE. 2019;14(4):e0215218.PubMedPubMedCentralCrossRef Dolor A, Sampson SL, Lazar AA, Lotz JC, Szoka FC, Fields AJ. Matrix modification for enhancing the transport properties of the human cartilage endplate to improve disc nutrition. PLoS ONE. 2019;14(4):e0215218.PubMedPubMedCentralCrossRef
22.
go back to reference Rinkler C, Heuer F, Pedro MT, Mauer UM, Ignatius A, Neidlinger-Wilke C. Influence of low glucose supply on the regulation of gene expression by nucleus pulposus cells and their responsiveness to mechanical loading. J Neurosurg Spine. 2010;13(4):535–42.PubMedCrossRef Rinkler C, Heuer F, Pedro MT, Mauer UM, Ignatius A, Neidlinger-Wilke C. Influence of low glucose supply on the regulation of gene expression by nucleus pulposus cells and their responsiveness to mechanical loading. J Neurosurg Spine. 2010;13(4):535–42.PubMedCrossRef
23.
go back to reference Jünger S, Gantenbein-Ritter B, Lezuo P, Alini M, Ferguson SJ, Ito K. Effect of limited nutrition on in situ intervertebral disc cells under simulated-physiological loading. Spine. 2009;34(12):1264–71.PubMedCrossRef Jünger S, Gantenbein-Ritter B, Lezuo P, Alini M, Ferguson SJ, Ito K. Effect of limited nutrition on in situ intervertebral disc cells under simulated-physiological loading. Spine. 2009;34(12):1264–71.PubMedCrossRef
24.
go back to reference Lang G, Liu Y, Geries J, Zhou Z, Kubosch D, Südkamp N, Richards RG, Alini M, Grad S, Li Z. An intervertebral disc whole organ culture system to investigate proinflammatory and degenerative disc disease condition. J Tissue Eng Regen Med. 2018;12(4):e2051–61.PubMedCrossRef Lang G, Liu Y, Geries J, Zhou Z, Kubosch D, Südkamp N, Richards RG, Alini M, Grad S, Li Z. An intervertebral disc whole organ culture system to investigate proinflammatory and degenerative disc disease condition. J Tissue Eng Regen Med. 2018;12(4):e2051–61.PubMedCrossRef
25.
go back to reference Park JH, Lee JS, Oh Y, Lee JS, Park HE, Lee H, Park YS, Kyung SY, Kim HS, Yoon S. PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity. In vivo (Athens Greece). 2022;36(2):694–703. Park JH, Lee JS, Oh Y, Lee JS, Park HE, Lee H, Park YS, Kyung SY, Kim HS, Yoon S. PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity. In vivo (Athens Greece). 2022;36(2):694–703.
26.
go back to reference Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function and expression and regulation. Cell & bioscience. 2019;9:52.CrossRef Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function and expression and regulation. Cell & bioscience. 2019;9:52.CrossRef
27.
go back to reference Gao J, Zhao Y, Li T, Gan X, Yu H. The Role of PKM2 in the Regulation of Mitochondrial Function: Focus on Mitochondrial Metabolism, Oxidative Stress, Dynamic, and Apoptosis. PKM2 in Mitochondrial Function. Oxidative Med Cell Longev. 2022;2022:7702681.CrossRef Gao J, Zhao Y, Li T, Gan X, Yu H. The Role of PKM2 in the Regulation of Mitochondrial Function: Focus on Mitochondrial Metabolism, Oxidative Stress, Dynamic, and Apoptosis. PKM2 in Mitochondrial Function. Oxidative Med Cell Longev. 2022;2022:7702681.CrossRef
28.
go back to reference Zong Y, Feng S, Cheng J, Yu C, Lu G. Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation. Cell Physiol biochemistry: Int J experimental Cell Physiol Biochem Pharmacol. 2017;41(2):784–94.CrossRef Zong Y, Feng S, Cheng J, Yu C, Lu G. Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation. Cell Physiol biochemistry: Int J experimental Cell Physiol Biochem Pharmacol. 2017;41(2):784–94.CrossRef
29.
go back to reference Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells. Trends Endocrinol Metab. 2017;28(11):794–806.PubMedPubMedCentralCrossRef Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells. Trends Endocrinol Metab. 2017;28(11):794–806.PubMedPubMedCentralCrossRef
30.
go back to reference Fan CL, Yao ZH, Ye MN, Fu LL, Zhu GN, Dai Y, Yao XS. Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway. J Cell Mol Med. 2020;24(2):1332–44.PubMedCrossRef Fan CL, Yao ZH, Ye MN, Fu LL, Zhu GN, Dai Y, Yao XS. Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway. J Cell Mol Med. 2020;24(2):1332–44.PubMedCrossRef
31.
go back to reference Huang W, Qiu S, Tong X, He Y, Wang Z, Dong Y. Activating transcription factor 4 is required for high glucose inhibits proliferation and differentiation of MC3T3-E1 cells. J Recept Signal Transduct Res. 2019;39(5–6):407–14.PubMedCrossRef Huang W, Qiu S, Tong X, He Y, Wang Z, Dong Y. Activating transcription factor 4 is required for high glucose inhibits proliferation and differentiation of MC3T3-E1 cells. J Recept Signal Transduct Res. 2019;39(5–6):407–14.PubMedCrossRef
32.
go back to reference Wang C, Huang Z, Du Y, Cheng Y, Chen S, Guo F. ATF4 regulates lipid metabolism and thermogenesis. Cell Res. 2010;20(2):174–84.PubMedCrossRef Wang C, Huang Z, Du Y, Cheng Y, Chen S, Guo F. ATF4 regulates lipid metabolism and thermogenesis. Cell Res. 2010;20(2):174–84.PubMedCrossRef
33.
go back to reference Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes. 2009;58(11):2565–73.PubMedPubMedCentralCrossRef Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes. 2009;58(11):2565–73.PubMedPubMedCentralCrossRef
34.
go back to reference Chen HW, Liu MQ, Zhang GZ, Zhang CY, Wang ZH, Lin AX, Kang JH, Liu WZ, Guo XD, Wang YD, et al: Proanthocyanidins inhibit the apoptosis and aging of nucleus pulposus cells through the PI3K/Akt pathway delaying intervertebral disc degeneration. Connective tissue research 2022:1–13. Chen HW, Liu MQ, Zhang GZ, Zhang CY, Wang ZH, Lin AX, Kang JH, Liu WZ, Guo XD, Wang YD, et al: Proanthocyanidins inhibit the apoptosis and aging of nucleus pulposus cells through the PI3K/Akt pathway delaying intervertebral disc degeneration. Connective tissue research 2022:1–13.
36.
go back to reference Zeng Z, Jing D, Zhang X, Duan Y, Xue F. Cyclic mechanical stretch promotes energy metabolism in osteoblast-like cells through an mTOR signaling-associated mechanism. Int J Mol Med. 2015;36(4):947–56.PubMedPubMedCentralCrossRef Zeng Z, Jing D, Zhang X, Duan Y, Xue F. Cyclic mechanical stretch promotes energy metabolism in osteoblast-like cells through an mTOR signaling-associated mechanism. Int J Mol Med. 2015;36(4):947–56.PubMedPubMedCentralCrossRef
37.
go back to reference Li X, Wang X, Hu Z, Chen Z, Li H, Liu X, Yong ZY, Wang S, Wei Z, Han Y, et al. Possible involvement of the oxLDL/LOX-1 system in the pathogenesis and progression of human intervertebral disc degeneration or herniation. Sci Rep. 2017;7(1):7403.PubMedPubMedCentralCrossRef Li X, Wang X, Hu Z, Chen Z, Li H, Liu X, Yong ZY, Wang S, Wei Z, Han Y, et al. Possible involvement of the oxLDL/LOX-1 system in the pathogenesis and progression of human intervertebral disc degeneration or herniation. Sci Rep. 2017;7(1):7403.PubMedPubMedCentralCrossRef
38.
go back to reference Illien-Jünger S, Gantenbein-Ritter B, Grad S, Lezuo P, Ferguson SJ, Alini M, Ito K. The combined effects of limited nutrition and high-frequency loading on intervertebral discs with endplates. Spine. 2010;35(19):1744–52.PubMedCrossRef Illien-Jünger S, Gantenbein-Ritter B, Grad S, Lezuo P, Ferguson SJ, Alini M, Ito K. The combined effects of limited nutrition and high-frequency loading on intervertebral discs with endplates. Spine. 2010;35(19):1744–52.PubMedCrossRef
39.
go back to reference Li X, Yang S, Han L, Mao K, Yang S. Ciliary IFT80 is essential for intervertebral disc development and maintenance. Faseb j. 2020;34(5):6741–56.PubMedCrossRef Li X, Yang S, Han L, Mao K, Yang S. Ciliary IFT80 is essential for intervertebral disc development and maintenance. Faseb j. 2020;34(5):6741–56.PubMedCrossRef
40.
go back to reference Chang H, Cai F, Zhang Y, Xue M, Liu L, Yang A, Liu X. Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway. Biomed pharmacotherapy = Biomedecine pharmacotherapie. 2017;89:529–35.CrossRef Chang H, Cai F, Zhang Y, Xue M, Liu L, Yang A, Liu X. Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway. Biomed pharmacotherapy = Biomedecine pharmacotherapie. 2017;89:529–35.CrossRef
41.
go back to reference Liu Y. Hydrogen peroxide induces nucleus pulposus cell apoptosis by ATF4/CHOP signaling pathway. Experimental and therapeutic medicine. 2020;20(4):3244–52.PubMedPubMedCentral Liu Y. Hydrogen peroxide induces nucleus pulposus cell apoptosis by ATF4/CHOP signaling pathway. Experimental and therapeutic medicine. 2020;20(4):3244–52.PubMedPubMedCentral
42.
go back to reference Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci USA. 2014;111(1):279–84.PubMedCrossRef Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci USA. 2014;111(1):279–84.PubMedCrossRef
43.
go back to reference Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145(5):732–44.PubMedPubMedCentralCrossRef Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145(5):732–44.PubMedPubMedCentralCrossRef
44.
go back to reference Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD, Thompson CB. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci USA. 2012;109(18):6904–9.PubMedPubMedCentralCrossRef Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD, Thompson CB. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci USA. 2012;109(18):6904–9.PubMedPubMedCentralCrossRef
45.
go back to reference Schoepflin ZR, Silagi ES, Shapiro IM, Risbud MV. PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2017;31(9):3831–47.CrossRef Schoepflin ZR, Silagi ES, Shapiro IM, Risbud MV. PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2017;31(9):3831–47.CrossRef
46.
go back to reference Johansen JL, Sager TN, Lotharius J, Witten L, Mørk A, Egebjerg J, Thirstrup K. HIF prolyl hydroxylase inhibition increases cell viability and potentiates dopamine release in dopaminergic cells. J Neurochem. 2010;115(1):209–19.PubMedCrossRef Johansen JL, Sager TN, Lotharius J, Witten L, Mørk A, Egebjerg J, Thirstrup K. HIF prolyl hydroxylase inhibition increases cell viability and potentiates dopamine release in dopaminergic cells. J Neurochem. 2010;115(1):209–19.PubMedCrossRef
47.
go back to reference Zhang X, Hu Z, Hao J, Shen J. Low Intensity Pulsed Ultrasound Promotes the Extracellular Matrix Synthesis of Degenerative Human Nucleus Pulposus Cells Through FAK/PI3K/Akt Pathway. Spine. 2016;41(5):E248–54.PubMedCrossRef Zhang X, Hu Z, Hao J, Shen J. Low Intensity Pulsed Ultrasound Promotes the Extracellular Matrix Synthesis of Degenerative Human Nucleus Pulposus Cells Through FAK/PI3K/Akt Pathway. Spine. 2016;41(5):E248–54.PubMedCrossRef
48.
go back to reference Lo WC, Chiou CS, Tsai FC, Chan CH, Mao S, Deng YH, Wu CY, Peng BY, Deng WP. Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis. Cell Transplant. 2021;30:9636897211045319.PubMedCrossRef Lo WC, Chiou CS, Tsai FC, Chan CH, Mao S, Deng YH, Wu CY, Peng BY, Deng WP. Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis. Cell Transplant. 2021;30:9636897211045319.PubMedCrossRef
49.
go back to reference Yang Y, Wang X, Liu Z, Xiao X, Hu W, Sun Z. Osteogenic protein-1 attenuates nucleus pulposus cell apoptosis through activating the PI3K/Akt/mTOR pathway in a hyperosmotic culture. Bioscience reports 2018, 38(6). Yang Y, Wang X, Liu Z, Xiao X, Hu W, Sun Z. Osteogenic protein-1 attenuates nucleus pulposus cell apoptosis through activating the PI3K/Akt/mTOR pathway in a hyperosmotic culture. Bioscience reports 2018, 38(6).
50.
go back to reference Zhao Y, Li A. miR-19b-3p relieves intervertebral disc degeneration through modulating PTEN/PI3K/Akt/mTOR signaling pathway. Aging. 2021;13(18):22459–73.PubMedPubMedCentralCrossRef Zhao Y, Li A. miR-19b-3p relieves intervertebral disc degeneration through modulating PTEN/PI3K/Akt/mTOR signaling pathway. Aging. 2021;13(18):22459–73.PubMedPubMedCentralCrossRef
51.
52.
go back to reference Riscal R, Schrepfer E, Arena G, Cissé MY, Bellvert F, Heuillet M, Rambow F, Bonneil E, Sabourdy F, Vincent C, et al: Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53. Molecular cell 2016, 62(6):890–902. Riscal R, Schrepfer E, Arena G, Cissé MY, Bellvert F, Heuillet M, Rambow F, Bonneil E, Sabourdy F, Vincent C, et al: Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53. Molecular cell 2016, 62(6):890–902.
53.
go back to reference Ganapathy-Kanniappan S, Kunjithapatham R, Geschwind JF. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting. Anticancer Res. 2013;33(1):13–20.PubMed Ganapathy-Kanniappan S, Kunjithapatham R, Geschwind JF. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting. Anticancer Res. 2013;33(1):13–20.PubMed
54.
go back to reference He S, Jia Q, Zhou L, Wang Z, Li M. SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis. Pathol Res Pract. 2022;235:153943.PubMedCrossRef He S, Jia Q, Zhou L, Wang Z, Li M. SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis. Pathol Res Pract. 2022;235:153943.PubMedCrossRef
Metadata
Title
Nutritional deficiency induces nucleus pulposus cell apoptosis via the ATF4-PKM2-AKT signal axis
Authors
Ningfeng Zhou
Bin Shen
Chong Bai
Liang Ma
Shanjin Wang
Desheng Wu
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2022
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-022-05853-1

Other articles of this Issue 1/2022

BMC Musculoskeletal Disorders 1/2022 Go to the issue