Intervertebral disc degeneration (IDD) is closely related to low back pain, which is a prevalent age-related problem worldwide; however, the mechanism underlying IDD is unknown. Glutamine, a free amino acid prevalent in plasma, is recognized for its anti-inflammatory and antioxidant properties in various diseases, and the current study aims to clarify the effect and mechanism of glutamine in IDD.
Results:
A synergistic interplay was observed between pyroptosis and ferroptosis within degenerated human disc specimens. Glutamine significantly mitigated IDD in both ex vivo and in vivo experimental models. Moreover, glutamine protected nucleus pulposus (NP) cells after tert-butyl hydroperoxide (TBHP)-induced pyroptosis, ferroptosis, and extracellular matrix (ECM) degradation in vitro. Glutamine protected NP cells from TBHP-induced ferroptosis by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitin–proteasome degradation and inhibiting lipid oxidation.
Innovation and Conclusions:
A direct correlation is evident in the progression of IDD between the processes of pyroptosis and ferroptosis. Glutamine suppressed oxidative stress-induced cellular processes, including pyroptosis, ferroptosis, and ECM degradation through deubiquitinating Nrf2 and inhibiting lipid oxidation in NP cells. Glutamine is a promising novel therapeutic target for the management of IDD.
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References
1.
AdamsMA, FreemanBJ, MorrisonHP, et al.Mechanical initiation of intervertebral disc degeneration. Spine (Phila Pa 1976), 2000; 25(13):1625–1636; doi: 10.1097/00007632-200007010-00005
2.
AdamsMA, RoughleyPJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976), 2006; 31(18):2151–2161; doi: 10.1097/01.brs.0000231761.73859.2c
3.
AhluwaliaGS, GremJL, HaoZ, et al.Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther, 1990; 46(2):243–271; doi: 10.1016/0163-7258(90)90094-i
4.
AnkerMS, HaverkampW, AnkerSD. A Phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med, 2018; 379(19):1879; doi: 10.1056/NEJMc1811050
BiswasS, LunecJ, BartlettK. Non-glucose metabolism in cancer cells–is it all in the fat? Cancer Metastasis Rev, 2012; 31(3-4):689–698; doi: 10.1007/s10555-012-9384-6
7.
Chao-YangG, PengC, Hai-HongZ. Roles of NLRP3 inflammasome in intervertebral disc degeneration. Osteoarthritis Cartilage, 2021; 29(6):793–801; doi: 10.1016/j.joca.2021.02.204
8.
ChenWW, FreinkmanE, WangT, et al.Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell, 2016; 166(5):1324–1337 e1311; doi: 10.1016/j.cell.2016.07.040
9.
ChenJ, YanJ, LiS, et al.Atorvastatin inhibited TNF-alpha induced matrix degradation in rat nucleus pulposus cells by suppressing NLRP3 inflammasome activity and inducing autophagy through NF-kappaB signaling. Cell Cycle, 2021; 20(20):2160–2173; doi: 10.1080/15384101.2021.1973707
10.
CuevasS, PelegrínP. Pyroptosis and redox balance in kidney diseases. Antioxid Redox Signal, 2021; 35(1):40–60; doi: 10.1089/ars.2020.8243
11.
DeBerardinisRJ, ChengT. Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 2010; 29(3):313–324; doi: 10.1038/onc.2009.358
12.
DengZ, ZhangY, ZhuY, et al.BRD9 inhibition attenuates matrix degradation and pyroptosis in nucleus pulposus by modulating the NOX1/ROS/NF-kappaB axis. Inflammation, 2023; 46(3):1002–1021; doi: 10.1007/s10753-023-01786-6
13.
DixonSJ, LembergKM, LamprechtMR, et al.Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012; 149(5):1060–1072; doi: 10.1016/j.cell.2012.03.042
14.
FanJ, KamphorstJJ, MathewR, et al.Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol, 2013; 9:712; doi: 10.1038/msb.2013.65
15.
GianolaS, BargeriS, Del CastilloG, et al.Effectiveness of treatments for acute and subacute mechanical non-specific low back pain: A systematic review with network meta-analysis. Br J Sports Med, 2022; 56(1):41–50; doi: 10.1136/bjsports-2020-103596
16.
GuX, WangY, HeY, et al.MiR-1656 targets GPX4 to trigger pyroptosis in broilers kidney tissues by activating NLRP3 inflammasome under Se deficiency. J Nutr Biochem, 2022; 105:109001; doi: 10.1016/j.jnutbio.2022.109001
17.
HeX, LaiQ, ChenC, et al.Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function. Diabetologia, 2018; 61(4):881–895; doi: 10.1007/s00125-017-4523-9
18.
HorngT. Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol, 2014; 35(6):253–261; doi: 10.1016/j.it.2014.02.007
19.
HoyD, MarchL, BrooksP, et al.The global burden of low back pain: Estimates from the global burden of disease 2010 study. Ann Rheum Dis, 2014; 73(6):968–974; doi: 10.1136/annrheumdis-2013-204428
20.
HsuCG, ChávezCL, ZhangC, et al.The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis. Cell Death Differ, 2022; 29(9):1790–1803; doi: 10.1038/s41418-022-00966-5
21.
HuangB, WuH, ZhengL, et al.Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598. Osteoarthritis Cartilage, 2023; 31(2):213–227; doi: 10.1016/j.joca.2022.10.008
22.
JeongSY, ImYN, YoumJY, et al.l-Glutamine attenuates DSS-Induced colitis via induction of MAPK Phosphatase-1. Nutrients, 2018; 10(3); doi: 10.3390/nu10030288
23.
JiangSJ, XiaoX, LiJ, et al.Lycium barbarum polysaccharide-glycoprotein ameliorates ionizing radiation-induced epithelial injury by regulating oxidative stress and ferroptosis via the Nrf2 pathway. Free Radic Biol Med, 2023; 204:84–94; doi: 10.1016/j.freeradbiomed.2023.04.020
KeorochanaG, JohnsonJS, TaghaviCE, et al.The effect of needle size inducing degeneration in the rat caudal disc: Evaluation using radiograph, magnetic resonance imaging, histology, and immunohistochemistry. Spine J, 2010; 10(11):1014–1023; doi: 10.1016/j.spinee.2010.08.013
26.
KnezevicNN, CandidoKD, VlaeyenJWS, et al.Low back pain. Lancet, 2021; 398(10294):78–92; doi: 10.1016/s0140-6736(21)00733-9
27.
LiS, LiaoZ, YinH, et al.G3BP1 coordinates lysophagy activity to protect against compression-induced cell ferroptosis during intervertebral disc degeneration. Cell Prolif, 2022; 56(3):e13368; doi: 10.1111/cpr.13368
28.
MaX, CaiD, ZhuY, et al.L-Glutamine alleviates osteoarthritis by regulating lncRNA-NKILA expression through the TGF-beta1/SMAD2/3 signalling pathway. Clin Sci (Lond), 2022b;136(13):1053–1069; doi: 10.1042/CS20220082
29.
MaH, XieC, ChenZ, et al.MFG-E8 alleviates intervertebral disc degeneration by suppressing pyroptosis and extracellular matrix degradation in nucleus pulposus cells via Nrf2/TXNIP/NLRP3 axis. Cell Death Discov, 2022a;8(1):209; doi: 10.1038/s41420-022-01002-8
30.
Powell-TuckJ. Total parenteral nutrition with glutamine dipeptide shortened hospital stays and improved immune status and nitrogen economy after major abdominal surgery. Gut, 1999; 44(2):155; doi: 10.1136/gut.44.2.155
31.
QinT, YanJ, LiS, et al.MicroRNA-155 suppressed cholesterol-induced matrix degradation, pyroptosis and apoptosis by targeting RORalpha in nucleus pulposus cells. Cell Signal, 2023; 107:110678; doi: 10.1016/j.cellsig.2023.110678
StegenS, RinaldiG, LoopmansS, et al.Glutamine metabolism controls chondrocyte identity and function. Dev Cell, 2020; 53(5):530–544. e538; doi: 10.1016/j.devcel.2020.05.001
35.
UrbanJP, RobertsS. Degeneration of the intervertebral disc. Arthritis Res Ther, 2003; 5(3):120–130; doi: 10.1186/ar629
36.
WangY, DuanH, ZhangJ, et al.YAP1 protects against PM2.5-induced lung toxicity by suppressing pyroptosis and ferroptosis. Ecotoxicol Environ Saf, 2023; 253:114708; doi: 10.1016/j.ecoenv.2023.114708
37.
WangX, LiuX, WangH. Combination regimen of granulocyte colony-stimulating factor and recombinant human thrombopoietin improves the curative effect on elderly patients with leukemia through inducing pyroptosis and ferroptosis of leukemia cells. Cancer Gene Ther, 2022; 29(11):1742–1750; doi: 10.1038/s41417-022-00497-8
38.
WelbourneTC. Ammonia production and glutamine incorporation into glutathione in the functioning rat kidney. Can J Biochem, 1979; 57(3):233–237; doi: 10.1139/o79-029
39.
WuJ, FengZ, ChenL, et al.TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat Commun, 2022; 13(1):676; doi: 10.1038/s41467-021-27948-4
40.
YanJ, LiS, ZhangY, et al.Cholesterol induces pyroptosis and matrix degradation via mSREBP1-driven endoplasmic reticulum stress in intervertebral disc degeneration. Front Cell Dev Biol, 2021; 9:803132; doi: 10.3389/fcell.2021.803132
41.
YangX, ChenY, GuoJ, et al.Polydopamine nanoparticles targeting ferroptosis mitigate intervertebral disc degeneration via reactive oxygen species depletion, iron ions chelation, and GPX4 Ubiquitination Suppression. Adv Sci (Weinh), 2023b;10(13):e2207216; doi: 10.1002/advs.202207216
42.
YangS, WangL, ZengY, et al.Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice. Phytomedicine, 2023a;114:154762; doi: 10.1016/j.phymed.2023.154762
43.
YangRZ, XuWN, ZhengHL, et al.Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis. J Cell Physiol, 2021; 236(4):2725–2739; doi: 10.1002/jcp.30039
44.
YoungVR, AjamiAM. Glutamine: The emperor or his clothes? J Nutr, 2001; 131(9 Suppl):2449S–2459S; doi: 10.1093/jn/131.9.2449Sdiscussion 2486S-2447S;
45.
YuanZ, LiuT, HuoX, et al.Glutamine transporter SLC1A5 regulates ionizing radiation-derived oxidative damage and ferroptosis. Oxid Med Cell Longev, 2022; 2022:3403009; doi: 10.1155/2022/3403009
46.
ZengX, YangM, YeT, et al.Mitochondrial GRIM-19 loss in parietal cells promotes spasmolytic polypeptide-expressing metaplasia through NLR family pyrin domain-containing 3 (NLRP3)-mediated IL-33 activation via a reactive oxygen species (ROS) -NRF2- Heme oxygenase-1(HO-1)-NF-кB axis. Free Radic Biol Med, 2023; 202:46–61; doi: 10.1016/j.freeradbiomed.2023.03.024
47.
ZhangS, HuB, LiuW, et al.The role of structure and function changes of sensory nervous system in intervertebral disc-related low back pain. Osteoarthritis Cartilage, 2021; 29(1):17–27; doi: 10.1016/j.joca.2020.09.002
48.
ZhangX, HuangZ, XieZ, et al.Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4. Free Radic Biol Med, 2020; 160:552–565; doi: 10.1016/j.freeradbiomed.2020.08.029
49.
ZhangF, LiuT, HuangHC, et al.Activation of pyroptosis and ferroptosis is involved in radiation-induced intestinal injury in mice. Biochem Biophys Res Commun, 2022; 631:102–109; doi: 10.1016/j.bbrc.2022.09.073
50.
ZhouB, ZhangJY, LiuXS, et al.Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res, 2018; 28(12):1171–1185; doi: 10.1038/s41422-018-0090-y
51.
ZhuJ, SunR, SunK, et al.The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3. Redox Biol, 2023a;62:102707; doi: 10.1016/j.redox.2023.102707
52.
ZhuJ, SunR, YanC, et al.Hesperidin mitigates oxidative stress-induced ferroptosis in nucleus pulposus cells via Nrf2/NF-kappaB axis to protect intervertebral disc from degeneration. Cell Cycle, 2023b;22(10):1196–1214; doi: 10.1080/15384101.2023.2200291
53.
ZiebaJ, ForlenzaKN, HeardK, et al.Intervertebral disc degeneration is rescued by TGFbeta/BMP signaling modulation in an ex vivo filamin B mouse model. Bone Res, 2022; 10(1):37; doi: 10.1038/s41413-022-00200-5
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