FGF23 alleviates neuronal apoptosis and inflammation, and promotes locomotion recovery via activation of PI3K/AKT signalling in spinal cord injury

Cui,Yan; Yang,Bin; Lin,Shaoyi; Huang,Luqiang; Xie,Feibin; Feng,Wei; Lin,Zhenzong

doi:10.3892/etm.2023.12039

FGF23 alleviates neuronal apoptosis and inflammation, and promotes locomotion recovery via activation of PI3K/AKT signalling in spinal cord injury

Authors:
- Yan Cui
- Bin Yang
- Shaoyi Lin
- Luqiang Huang
- Feibin Xie
- Wei Feng
- Zhenzong Lin
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Affiliations: Department of Orthopaedic Trauma, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China, Department of Neurosurgery, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
Published online on: May 22, 2023 https://doi.org/10.3892/etm.2023.12039
Article Number: 340
Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fibroblast growth factor 23 (FGF23) regulates neuronal morphology, synaptic growth and inflammation; however, its involvement in spinal cord injury (SCI) remains unclear. Therefore, the present study aimed to investigate the effect of FGF23 on neuronal apoptosis, inflammation and locomotion recovery, as well as its underlying mechanism in experimental SCI models. Primary rat neurons were stimulated with H2O2 to establish an in vitro model of SCI and were then transfected with an FGF23 overexpression (oeFGF23) or short hairpin RNA (shFGF23) adenovirus‑associated virus and treated with or without LY294002 (a PI3K/AKT inhibitor). Subsequently, an SCI rat model was constructed, followed by treatment with oeFGF23, LY294002 or a combination of the two. FGF23 overexpression (oeFGF23 vs. oeNC) decreased the cell apoptotic rate and cleaved‑caspase3 expression, but increased Bcl‑2 expression in H2O2‑stimulated neurons, whereas shFGF23 transfection (shFGF23 vs. shNC) exhibited the opposite effect (all P<0.05). Furthermore, FGF23 overexpression (oeFGF23 vs. oeNC) could activate the PI3K/AKT signalling pathway, whereas treatment with the PI3K/AKT inhibitor (LY294002) (oeFGF23 + LY294002 vs. LY294002) attenuated these effects in H2O2‑stimulated neurons (all P<0.05). In SCI model rats, FGF23 overexpression (oeFGF23 vs. oeNC) reduced the laceration and inflammatory cell infiltration in injured tissue, decreased TNF‑α and IL‑1β levels, and improved locomotion recovery (all P<0.05); these effects were attenuated by additional administration of LY294002 (oeFGF23 + LY294002 vs. LY294002) (all P<0.05). In conclusion, FGF23 alleviated neuronal apoptosis and inflammation, and promoted locomotion recovery via activation of the PI3K/AKT signalling pathway in SCI, indicating its potential as a treatment option for SCI; however, further studies are warranted for validation.

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1	Hachem LD and Fehlings MG: Pathophysiology of spinal cord injury. Neurosurg Clin N Am. 32:305–313. 2021.PubMed/NCBI View Article : Google Scholar
2	Lee BJ and Jeong JH: Review: Steroid use in patients with acute spinal cord injury and guideline update. Korean J Neurotrauma. 18:22–30. 2022.PubMed/NCBI View Article : Google Scholar
3	Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, Ismail OHR, Athi Kumar RK and Lokanathan Y: Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 21(7533)2020.PubMed/NCBI View Article : Google Scholar
4	Eli I, Lerner DP and Ghogawala Z: Acute traumatic spinal cord injury. Neurol Clin. 39:471–488. 2021.PubMed/NCBI View Article : Google Scholar
5	Karsy M and Hawryluk G: Modern medical management of spinal cord injury. Curr Neurol Neurosci Rep. 19(65)2019.PubMed/NCBI View Article : Google Scholar
6	Huang H, Young W, Skaper S, Chen L, Moviglia G, Saberi H, Al-Zoubi Z, Sharma HS, Muresanu D, Sharma A, et al: Clinical neurorestorative therapeutic guidelines for spinal cord injury (IANR/CANR version 2019). J Orthop Translat. 20:14–24. 2019.PubMed/NCBI View Article : Google Scholar
7	Patsakos EM, Bayley MT, Kua A, Cheng C, Eng J, Ho C, Noonan VK, Querée M and Craven BC: Can-SCIP Guideline Expert Panel. Development of the Canadian spinal cord injury best practice (Can-SCIP) guideline: Methods and overview. J Spinal Cord Med. 44 (Suppl 1):S52–S68. 2021.PubMed/NCBI View Article : Google Scholar
8	Alam R, Mrad Y, Hammoud H, Saker Z, Fares Y, Estephan E, Bahmad HF, Harati H and Nabha S: New insights into the role of fibroblast growth factors in Alzheimer's disease. Mol Biol Rep. 49:1413–1427. 2022.PubMed/NCBI View Article : Google Scholar
9	Klimaschewski L and Claus P: Fibroblast growth factor signalling in the diseased nervous system. Mol Neurobiol. 58:3884–3902. 2021.PubMed/NCBI View Article : Google Scholar
10	Vervloet MG: Shedding light on the complex regulation of FGF23. Metabolites. 12(401)2022.PubMed/NCBI View Article : Google Scholar
11	Hensel N, Schön A, Konen T, Lübben V, Förthmann B, Baron O, Grothe C, Leifheit-Nestler M, Claus P and Haffner D: Fibroblast growth factor 23 signaling in hippocampal cells: Impact on neuronal morphology and synaptic density. J Neurochem. 137:756–769. 2016.PubMed/NCBI View Article : Google Scholar
12	Oshima N, Onimaru H, Yamagata A, Ito S, Imakiire T and Kumagai H: Rostral ventrolateral medulla neuron activity is suppressed by Klotho and stimulated by FGF23 in newborn Wistar rats. Auton Neurosci. 224(102640)2020.PubMed/NCBI View Article : Google Scholar
13	Musgrove J and Wolf M: Regulation and effects of FGF23 in chronic kidney disease. Annu Rev Physiol. 82:365–390. 2020.PubMed/NCBI View Article : Google Scholar
14	Zhang X, Guo K, Xia F, Zhao X, Huang Z and Niu J: FGF23^C-tail improves diabetic nephropathy by attenuating renal fibrosis and inflammation. BMC Biotechnol. 18(33)2018.PubMed/NCBI View Article : Google Scholar
15	Guidelines for Endpoints in Animal Study Proposals. Available at: https://oacu.oir.nih.gov/system/files/media/file/2022-04/b13_endpoints_guidelines.pdf.
16	Yang H, Wang H, Shu Y and Li X: miR-103 promotes neurite outgrowth and suppresses cells apoptosis by targeting prostaglandin-endoperoxide synthase 2 in cellular models of Alzheimer's disease. Front Cell Neurosci. 12(91)2018.PubMed/NCBI View Article : Google Scholar
17	Wang N, Yang Y, Pang M, Du C, Chen Y, Li S, Tian Z, Feng F, Wang Y, Chen Z, et al: MicroRNA-135a-5p promotes the functional recovery of spinal cord injury by targeting SP1 and ROCK. Mol Ther Nucleic Acids. 22:1063–1077. 2020.PubMed/NCBI View Article : Google Scholar
18	Luo Z, Wu F, Xue E, Huang L, Yan P, Pan X and Zhou Y: Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system. Cell Death Dis. 10(134)2019.PubMed/NCBI View Article : Google Scholar
19	Zhao R, Wu X, Bi XY, Yang H and Zhang Q: Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury. Neural Regen Res. 17:1080–1087. 2022.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Li X, Zhang C, Haggerty AE, Yan J, Lan M, Seu M, Yang M, Marlow MM, Maldonado-Lasunción I, Cho B, et al: The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord. Biomaterials. 245(119978)2020.PubMed/NCBI View Article : Google Scholar
22	Chen J, Wang Z, Zheng Z, Chen Y, Khor S, Shi K, He Z, Wang Q, Zhao Y, Zhang H, et al: Neuron and microglia/macrophage-derived FGF10 activate neuronal FGFR2/PI3K/Akt signaling and inhibit microglia/macrophages TLR4/NF-κB-dependent neuroinflammation to improve functional recovery after spinal cord injury. Cell Death Dis. 8(e3090)2017.PubMed/NCBI View Article : Google Scholar
23	Wang H, Zheng Z, Han W, Yuan Y, Li Y, Zhou K, Wang Q, Xie L, Xu K, Zhang H, et al: Metformin promotes axon regeneration after spinal cord injury through inhibiting oxidative stress and stabilizing microtubule. Oxid Med Cell Longev. 2020(9741369)2020.PubMed/NCBI View Article : Google Scholar
24	AVMA Guidelines for the Euthanasia of Animals: 2020 Edition. Available at: https://olaw.nih.gov/avma-guidelines-2020.htm.
25	Nagashima K, Miwa T, Soumiya H, Ushiro D, Takeda-Kawaguchi T, Tamaoki N, Ishiguro S, Sato Y, Miyamoto K, Ohno T, et al: Priming with FGF2 stimulates human dental pulp cells to promote axonal regeneration and locomotor function recovery after spinal cord injury. Sci Rep. 7(13500)2017.PubMed/NCBI View Article : Google Scholar
26	Vargas MR, Pehar M, Cassina P, Martínez-Palma L, Thompson JA, Beckman JS and Barbeito L: Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: Consequences for motor neuron survival. J Biol Chem. 280:25571–25579. 2005.PubMed/NCBI View Article : Google Scholar
27	Kma L and Baruah TJ: The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem. 69:248–264. 2022.PubMed/NCBI View Article : Google Scholar
28	Xiao Z, King G, Mancarella S, Munkhsaikhan U, Cao L, Cai C and Quarles LD: FGF23 expression is stimulated in transgenic alpha-Klotho longevity mouse model. JCI Insight. 4(e132820)2019.PubMed/NCBI View Article : Google Scholar
29	Mills S: Histology for Pathologists (5th edition). Wolters Kluwer health, chapter 9, pp224-232, 2019.
30	Jiang D, Gong F, Ge X, Lv C, Huang C, Feng S, Zhou Z, Rong Y, Wang J, Ji C, et al: Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes. J Nanobiotechnology. 18(105)2020.PubMed/NCBI View Article : Google Scholar
31	Xu S, Wang J, Zhong J, Shao M, Jiang J, Song J, Zhu W, Zhang F, Xu H, Xu G, et al: CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling. Clin Transl Med. 11(e269)2021.PubMed/NCBI View Article : Google Scholar
32	Luo W, Jiang Y, Yi Z, Wu Y, Gong P and Xiong Y: 1a,25-Dihydroxyvitamin D³ promotes osteogenesis by down-regulating FGF23 in diabetic mice. J Cell Mol Med. 25:4148–4156. 2021.PubMed/NCBI View Article : Google Scholar
33	Xiao Z, Huang J, Cao L, Liang Y, Han X and Quarles LD: Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One. 9(e104154)2014.PubMed/NCBI View Article : Google Scholar
34	O'Shea TM, Burda JE and Sofroniew MV: Cell biology of spinal cord injury and repair. J Clin Invest. 127:3259–3270. 2017.PubMed/NCBI View Article : Google Scholar
35	Hellenbrand DJ, Quinn CM, Piper ZJ, Morehouse CN, Fixel JA and Hanna AS: Inflammation after spinal cord injury: A review of the critical timeline of signaling cues and cellular infiltration. J Neuroinflammation. 18(284)2021.PubMed/NCBI View Article : Google Scholar