Metformin Decreases LPS-induced Inflammatory Response in Rabbit Annulus Fibrosus Stem/progenitor Cells by Blocking HMGB1 Release

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2019 Nov 28

PMID 31772144

Citations 32

Authors

Yingchao Han

Feng Yuan

Chao Deng

Fan He

Yan Zhang

Hongxing Shen

Zhi Chen

Lie Qian

Affiliations

Soon will be listed here.

Abstract

The present study aimed to investigate the mechanism of intervertebral disc degeneration (IVDD) and identify an efficient treatment for low back pain. Rabbit annulus fibrosus stem cells (AFSCs) were treated with metformin and lipopolysaccharide (LPS). The results indicated that LPS induced HMGB1 release from the nuclei of AFSCs and caused cell senescence in a concentration-dependent manner. The production of PGE2 and HMGB1 was increased in the medium of the LPS-treated AFSCs. Certain inflammation-associated genes (, , and α) and proteins (IL-β1, COX-2 and TNF-α) and specific catabolic genes ( and ) exhibited increased expression in LPS-treated AFSCs. However, the expression levels of other anabolic genes, such as and were decreased in LPS-treated AFSCs. Following addition of metformin to LPS-containing medium, HMGB1 was retained in the nuclei of AFSCs and the production of PGE2 and HMGB1 was reduced. The expression levels of the catabolic genes and proteins were decreased and those of the anabolic genes were increased. The findings indicated that metformin exerted an anti-inflammatory effect by blocking the HMGB1 translocation and by inhibiting catabolic production and cell senescence in AFSCs. Therefore, metformin may be used as an efficient treatment for the disc degenerative disease.

Citing Articles

Discogenic Low Back Pain: Anatomic and Pathophysiologic Characterization, Clinical Evaluation, Biomarkers, AI, and Treatment Options.

De Simone M, Choucha A, Ciaglia E, Conti V, Pecoraro G, Santurro A J Clin Med. 2024; 13(19).

PMID: 39407975 PMC: 11477864. DOI: 10.3390/jcm13195915.

Current Therapeutic Strategies of Intervertebral Disc Regenerative Medicine.

Elmounedi N, Bahloul W, Keskes H Mol Diagn Ther. 2024; 28(6):745-775.

PMID: 39158834 DOI: 10.1007/s40291-024-00729-7.

Metformin prevents the onset and progression of intervertebral disc degeneration: New insights and potential mechanisms (Review).

Yang W, Yang Y, Wang Y, Gao Z, Zhang J, Gao W Int J Mol Med. 2024; 54(2).

PMID: 38963023 PMC: 11232665. DOI: 10.3892/ijmm.2024.5395.

Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII-Ampk pathway in aged mice.

Chen M, Li F, Qu M, Jin X, He T, He S Aging Cell. 2024; 23(9):e14237.

PMID: 38840443 PMC: 11488325. DOI: 10.1111/acel.14237.

Sirtuins in intervertebral disc degeneration: current understanding.

Shen J, Lan Y, Ji Z, Liu H Mol Med. 2024; 30(1):44.

PMID: 38553713 PMC: 10981339. DOI: 10.1186/s10020-024-00811-0.

References

Li Q, Li J, Wen T, Zeng W, Peng C, Yan S . Overexpression of HMGB1 in melanoma predicts patient survival and suppression of HMGB1 induces cell cycle arrest and senescence in association with p21 (Waf1/Cip1) up-regulation via a p53-independent, Sp1-dependent pathway. Oncotarget. 2014; 5(15):6387-403. PMC: 4171638. DOI: 10.18632/oncotarget.2201. View

Son S, Shin H, Byun J, Kook S, Moon M, Chang Y . Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. J Alzheimers Dis. 2016; 51(4):1197-208. DOI: 10.3233/JAD-151200. View

Appavoo E, Hajam I, Muneeswaran N, Kondabattula G, Bhanuprakash V, Kishore S . Synergistic effect of high-mobility group box-1 and lipopolysaccharide on cytokine induction in bovine peripheral blood mononuclear cells. Microbiol Immunol. 2015; 60(3):196-202. DOI: 10.1111/1348-0421.12350. View

Hu M, Ye P, Liao H, Chen M, Yang F . Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK. J Diabetes Res. 2016; 2016:2961954. PMC: 4884853. DOI: 10.1155/2016/2961954. View

Feng Y, Egan B, Wang J . Genetic Factors in Intervertebral Disc Degeneration. Genes Dis. 2016; 3(3):178-185. PMC: 5016799. DOI: 10.1016/j.gendis.2016.04.005. View

Liu J, Tao H, Wang H, Dong F, Zhang R, Li J . Biological Behavior of Human Nucleus Pulposus Mesenchymal Stem Cells in Response to Changes in the Acidic Environment During Intervertebral Disc Degeneration. Stem Cells Dev. 2017; 26(12):901-911. DOI: 10.1089/scd.2016.0314. View

Bailey C, Turner R . Metformin. N Engl J Med. 1996; 334(9):574-9. DOI: 10.1056/NEJM199602293340906. View

Tang D, Kang R, Van Houten B, Zeh H, Billiar T, Lotze M . High mobility group box 1 (HMGB1) phenotypic role revealed with stress. Mol Med. 2014; 20:359-62. PMC: 4153844. DOI: 10.2119/molmed.2014.00063. View

Yanai H, Matsuda A, An J, Koshiba R, Nishio J, Negishi H . Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A. 2013; 110(51):20699-704. PMC: 3870753. DOI: 10.1073/pnas.1320808110. View

10.

Teichtahl A, Urquhart D, Wang Y, Wluka A, OSullivan R, Jones G . Lumbar disc degeneration is associated with modic change and high paraspinal fat content - a 3.0T magnetic resonance imaging study. BMC Musculoskelet Disord. 2016; 17(1):439. PMC: 5073831. DOI: 10.1186/s12891-016-1297-z. View

11.

Zhong Y, Huang Y, Santoso M, Wu L . Sclareol exerts anti-osteoarthritic activities in interleukin-1β-induced rabbit chondrocytes and a rabbit osteoarthritis model. Int J Clin Exp Pathol. 2015; 8(3):2365-74. PMC: 4440052. View

12.

Katayama R, Wakitani S, Tsumaki N, Morita Y, Matsushita I, Gejo R . Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow. Rheumatology (Oxford). 2004; 43(8):980-5. DOI: 10.1093/rheumatology/keh240. View

13.

Wang J, Markova D, Anderson D, Zheng Z, Shapiro I, Risbud M . TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem. 2011; 286(46):39738-49. PMC: 3220535. DOI: 10.1074/jbc.M111.264549. View

14.

Molinos M, Almeida C, Caldeira J, Cunha C, Goncalves R, Barbosa M . Inflammation in intervertebral disc degeneration and regeneration. J R Soc Interface. 2015; 12(108):20150429. PMC: 4528607. DOI: 10.1098/rsif.2015.0429. View

15.

Li J, Gui Y, Ren J, Liu X, Feng Y, Zeng Z . Metformin Protects Against Cisplatin-Induced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKα-regulated Autophagy Induction. Sci Rep. 2016; 6:23975. PMC: 4823749. DOI: 10.1038/srep23975. View

16.

Kalariya N, Shoeb M, Ansari N, Srivastava S, Ramana K . Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2012; 53(7):3431-40. PMC: 3390006. DOI: 10.1167/iovs.12-9432. View

17.

Dumitriu I, Bianchi M, Bacci M, Manfredi A, Rovere-Querini P . The secretion of HMGB1 is required for the migration of maturing dendritic cells. J Leukoc Biol. 2006; 81(1):84-91. DOI: 10.1189/jlb.0306171. View

18.

Venereau E, Schiraldi M, Uguccioni M, Bianchi M . HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2012; 55(1):76-82. DOI: 10.1016/j.molimm.2012.10.037. View

19.

Hyun B, Shin S, Lee A, Lee S, Song Y, Ha N . Metformin Down-regulates TNF-α Secretion via Suppression of Scavenger Receptors in Macrophages. Immune Netw. 2013; 13(4):123-32. PMC: 3759709. DOI: 10.4110/in.2013.13.4.123. View

20.

Guerrero A, Gil J . HMGB2 holds the key to the senescence-associated secretory phenotype. J Cell Biol. 2016; 215(3):297-299. PMC: 5100298. DOI: 10.1083/jcb.201610044. View