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S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells

  • Authors:
    • Zhen Tian
    • Haoran Gao
    • Wenjun Xia
    • Zhaohui Lou
  • View Affiliations / Copyright

    Affiliations: Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
    Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 265
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    Published online on: April 25, 2024
       https://doi.org/10.3892/etm.2024.12553
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Abstract

Sphingosine 1‑phosphate receptor 3 (S1PR3) participates in the inflammatory response in multiple types of diseases. However, the biological role of S1PR3 in intervertebral disc degeneration and the underlying mechanism are unclear. The aim of the present study was to investigate the functional role and the mechanism of S1PR3 in lipopolysaccharide (LPS)‑induced human nucleus pulposus cells. The expression of S1PR3 and Toll‑like receptor (TLR) 2 in LPS‑induced nucleus pulposus (NP) cells was investigated using western blotting. The Cell Counting Kit‑8 assay was used to detect cell proliferation, and the levels of inflammatory factors were detected using ELISA. Flow cytometry and western blotting were used for the assessment of apoptosis. The deposition of extracellular matrix (ECM) proteins was investigated using reverse transcription‑quantitative PCR and western blotting. In addition, western blotting was used to investigate the protein expression levels of phosphorylated (p)‑STAT3, STAT3, p‑JNK, JNK, p‑ERK, ERK, p‑p38 and p38associated with STAT3 and MAPK signaling. S1PR3 expression was reduced, while TLR2 expression was elevated in LPS‑induced human nucleus pulposus cells (HNPC). S1PR3 overexpression increased HNPC viability, inhibited the inflammatory response and suppressed apoptosis. Meanwhile, S1PR3 overexpression regulated the expression of ECM‑related proteins. Additionally, overexpression of S1PR3 inhibited the expression of the TLR2‑regulated STAT3 and MAPK pathways in LPS‑induced HNPCs. Furthermore, TLR2 overexpression partially offset the impacts of S1PR3 overexpression on HNPC viability, apoptosis level, inflammation and as ECM degradation. In conclusion, STAT3 overexpression suppressed viability injury, the inflammatory response and the level of apoptosis and alleviated ECM protein deposition in HNPCs through the TLR2/STAT3 and TLR2/MAPK pathways, which may offer a promising candidate for the amelioration of intervertebral disc degeneration.
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1 

Urits I, Burshtein A, Sharma M, Testa L, Gold PA, Orhurhu V, Viswanath O, Jones MR, Sidransky MA, Spektor B and Kaye AD: Low back pain, a comprehensive review: Pathophysiology, diagnosis, and treatment. Curr Pain Headache Rep. 23(23)2019.PubMed/NCBI View Article : Google Scholar

2 

Will JS, Bury DC and Miller JA: Mechanical low back pain. Am Fam Physician. 98:421–428. 2018.PubMed/NCBI

3 

Vlaeyen JWS, Maher CG, Wiech K, Van Zundert J, Meloto CB, Diatchenko L, Battié MC, Goossens M, Koes B and Linton SJ: Low back pain. Nat Rev Dis Primers. 4(52)2018.PubMed/NCBI View Article : Google Scholar

4 

Xin J, Wang Y, Zheng Z, Wang S, Na S and Zhang S: Treatment of intervertebral disc degeneration. Orthop Surg. 14:1271–1280. 2022.PubMed/NCBI View Article : Google Scholar

5 

Chen S, Fu P, Wu H and Pei M: Meniscus, articular cartilage and nucleus pulposus: A comparative review of cartilage-like tissues in anatomy, development and function. Cell Tissue Res. 370:53–70. 2017.PubMed/NCBI View Article : Google Scholar

6 

Bhujel B, Shin HE, Choi DJ and Han I: Mesenchymal stem cell-derived exosomes and intervertebral disc regeneration: Review. Int J Mol Sci. 23(7306)2022.PubMed/NCBI View Article : Google Scholar

7 

Kirnaz S, Capadona C, Wong T, Goldberg JL, Medary B, Sommer F, McGrath LB Jr and Härtl R: Fundamentals of intervertebral disc degeneration. World Neurosurg. 157:264–273. 2022.PubMed/NCBI View Article : Google Scholar

8 

Risbud MV and Shapiro IM: Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nat Rev Rheumatol. 10:44–56. 2014.PubMed/NCBI View Article : Google Scholar

9 

Vergroesen PP, Kingma I, Emanuel KS, Hoogendoorn RJ, Welting TJ, van Royen BJ, van Dieën JH and Smit TH: Mechanics and biology in intervertebral disc degeneration: A vicious circle. Osteoarthritis Cartilage. 23:1057–1070. 2015.PubMed/NCBI View Article : Google Scholar

10 

Krut Z, Pelled G, Gazit D and Gazit Z: Stem cells and exosomes: New therapies for intervertebral disc degeneration. Cells. 10(2241)2021.PubMed/NCBI View Article : Google Scholar

11 

Cartier A and Hla T: Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science. 366(eaar5551)2019.PubMed/NCBI View Article : Google Scholar

12 

Meshcheryakova A, Mechtcheriakova D and Pietschmann P: Sphingosine 1-phosphate signaling in bone remodeling: Multifaceted roles and therapeutic potential. Expert Opin Ther Targets. 21:725–737. 2017.PubMed/NCBI View Article : Google Scholar

13 

Hu Y, Yang C, Shen G, Yang S, Cheng X, Cheng F, Rao J and Wang X: Hyperglycemia-triggered sphingosine-1-phosphate and sphingosine-1-phosphate receptor 3 signaling worsens liver ischemia/reperfusion injury by regulating M1/M2 polarization. Liver Transpl. 25:1074–1090. 2019.PubMed/NCBI View Article : Google Scholar

14 

Weigel C, Hüttner SS, Ludwig K, Krieg N, Hofmann S, Schröder NH, Robbe L, Kluge S, Nierhaus A, Winkler MS, et al: S1P lyase inhibition protects against sepsis by promoting disease tolerance via the S1P/S1PR3 axis. EBioMedicine. 58(102898)2020.PubMed/NCBI View Article : Google Scholar

15 

Hou J, Chen Q, Wu X, Zhao D, Reuveni H, Licht T, Xu M, Hu H, Hoeft A, Ben-Sasson SA, et al: S1PR3 signaling drives bacterial killing and is required for survival in bacterial sepsis. Am J Respir Crit Care Med. 196:1559–1570. 2017.PubMed/NCBI View Article : Google Scholar

16 

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

17 

Yurube T, Takada T, Hirata H, Kakutani K, Maeno K, Zhang Z, Yamamoto J, Doita M, Kurosaka M and Nishida K: Modified house-keeping gene expression in a rat tail compression loading-induced disc degeneration model. J Orthop Res. 29:1284–1290. 2011.PubMed/NCBI View Article : Google Scholar

18 

Francisco V, Pino J, González-Gay M, Lago F, Karppinen J, Tervonen O, Mobasheri A and Gualillo O: A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol. 18:47–60. 2022.PubMed/NCBI View Article : Google Scholar

19 

Li Z, Chen X, Xu D, Li S, Chan MTV and Wu WKK: Circular RNAs in nucleus pulposus cell function and intervertebral disc degeneration. Cell Prolif. 52(e12704)2019.PubMed/NCBI View Article : Google Scholar

20 

He R, Wang Z, Cui M, Liu S, Wu W, Chen M, Wu Y, Qu Y, Lin H, Chen S, et al: HIF1A Alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy. Autophagy. 17:3338–3360. 2021.PubMed/NCBI View Article : Google Scholar

21 

Shao Z, Wang B, Shi Y, Xie C, Huang C, Chen B, Zhang H, Zeng G, Liang H, Wu Y, et al: Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis. Osteoarthritis Cartilage. 29:413–422. 2021.PubMed/NCBI View Article : Google Scholar

22 

Li Z, Yu X, Shen J, Chan MT and Wu WK: MicroRNA in intervertebral disc degeneration. Cell Prolif. 48:278–283. 2015.PubMed/NCBI View Article : Google Scholar

23 

Lin J, Du J, Wu X, Xu C, Liu J, Jiang L, Cheng X, Ge G, Chen L, Pang Q, et al: SIRT3 mitigates intervertebral disc degeneration by delaying oxidative stress-induced senescence of nucleus pulposus cells. J Cell Physiol. 236:6441–6456. 2021.PubMed/NCBI View Article : Google Scholar

24 

Kunkel GT, Maceyka M, Milstien S and Spiegel S: Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 12:688–702. 2013.PubMed/NCBI View Article : Google Scholar

25 

Muppidi JR, Lu E and Cyster JG: The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination. J Exp Med. 212:2213–2222. 2015.PubMed/NCBI View Article : Google Scholar

26 

Bajwa A, Huang L, Kurmaeva E, Gigliotti JC, Ye H, Miller J, Rosin DL, Lobo PI and Okusa MD: Sphingosine 1-phosphate receptor 3-deficient dendritic cells modulate splenic responses to ischemia-reperfusion injury. J Am Soc Nephrol. 27:1076–1090. 2016.PubMed/NCBI View Article : Google Scholar

27 

Nussbaum C, Bannenberg S, Keul P, Gräler MH, Gonçalves-de-Albuquerque CF, Korhonen H, von Wnuck Lipinski K, Heusch G, de Castro Faria Neto HC, Rohwedder I, et al: Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin. Nat Commun. 6(6416)2015.PubMed/NCBI View Article : Google Scholar

28 

Dong YF, Guo RB, Ji J, Cao LL, Zhang L, Chen ZZ, Huang JY, Wu J, Lu J and Sun XL: S1PR3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen-glucose deprivation-induced neuroinflammation via inhibiting TLR2/4-NFκB signalling. J Cell Mol Med. 22:3159–3166. 2018.PubMed/NCBI View Article : Google Scholar

29 

Yang K, Li H and Li C: Expression and role of Sphingosine 1-phosphate receptors in intervertebral disc degeneration. J Back Musculoskelet Rehabil. 33:255–262. 2020.PubMed/NCBI View Article : Google Scholar

30 

Lin Y, Jiao Y, Yuan Y, Zhou Z, Zheng Y, Xiao J, Li C, Chen Z and Cao P: Propionibacterium acnes induces intervertebral disc degeneration by promoting nucleus pulposus cell apoptosis via the TLR2/JNK/mitochondrial-mediated pathway. Emerg Microbes Infect. 7(1)2018.PubMed/NCBI View Article : Google Scholar

31 

Yang H, Tian W, Wang S, Liu X, Wang Z, Hou L, Ge J, Zhang X, He Z and Wang X: TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-κB signaling pathway. Lab Invest. 98:755–772. 2018.PubMed/NCBI View Article : Google Scholar

32 

Jin Y, Nguyen TLL, Myung CS and Heo KS: Ginsenoside Rh1 protects human endothelial cells against lipopolysaccharide-induced inflammatory injury through inhibiting TLR2/4-mediated STAT3, NF-κB, and ER stress signaling pathways. Life Sci. 309(120973)2022.PubMed/NCBI View Article : Google Scholar

33 

Xu Z, Hao X, Li M and Luo H: Rhodococcus equi-derived extracellular vesicles promoting inflammatory response in macrophage through TLR2-NF-κB/MAPK pathways. Int J Mol Sci. 23(9742)2022.PubMed/NCBI View Article : Google Scholar

34 

Wu C, Ge J, Yang M, Yan Q, Wang Y, Yu H, Yang H and Zou J: Resveratrol protects human nucleus pulposus cells from degeneration by blocking IL-6/JAK/STAT3 pathway. Eur J Med Res. 26(81)2021.PubMed/NCBI View Article : Google Scholar

35 

Sun K, Zhu J, Yan C, Li F, Kong F, Sun J, Sun X, Shi J and Wang Y: CGRP regulates nucleus pulposus cell apoptosis and inflammation via the MAPK/NF-κB signaling pathways during intervertebral disc degeneration. Oxid Med Cell Longev. 2021(2958584)2021.PubMed/NCBI View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Tian Z, Gao H, Xia W and Lou Z: S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells. Exp Ther Med 27: 265, 2024.
APA
Tian, Z., Gao, H., Xia, W., & Lou, Z. (2024). S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells. Experimental and Therapeutic Medicine, 27, 265. https://doi.org/10.3892/etm.2024.12553
MLA
Tian, Z., Gao, H., Xia, W., Lou, Z."S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells". Experimental and Therapeutic Medicine 27.6 (2024): 265.
Chicago
Tian, Z., Gao, H., Xia, W., Lou, Z."S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells". Experimental and Therapeutic Medicine 27, no. 6 (2024): 265. https://doi.org/10.3892/etm.2024.12553
Copy and paste a formatted citation
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Spandidos Publications style
Tian Z, Gao H, Xia W and Lou Z: S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells. Exp Ther Med 27: 265, 2024.
APA
Tian, Z., Gao, H., Xia, W., & Lou, Z. (2024). S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells. Experimental and Therapeutic Medicine, 27, 265. https://doi.org/10.3892/etm.2024.12553
MLA
Tian, Z., Gao, H., Xia, W., Lou, Z."S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells". Experimental and Therapeutic Medicine 27.6 (2024): 265.
Chicago
Tian, Z., Gao, H., Xia, W., Lou, Z."S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells". Experimental and Therapeutic Medicine 27, no. 6 (2024): 265. https://doi.org/10.3892/etm.2024.12553
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