Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

General Research Article

Ezetimibe Prevents IL-1β-induced Inflammatory Reaction in Mouse Chondrocytes via Modulating NF-κB and Nrf2/HO-1 Signaling Crosstalk

Author(s): Qiuyan Weng, Tongzhou Hu, Xiaohan Shen, Jinming Han, Yong Zhang* and Jianning Luo*

Volume 23, Issue 14, 2022

Published on: 29 April, 2022

Page: [1772 - 1780] Pages: 9

DOI: 10.2174/1389201023666220104141521

Price: $65

Abstract

Background: Osteoarthritis is a type of age-related, chronic, and degenerative joint disease. Ezetimibe, a cholesterol absorption inhibitor, is widely used for the treatment of various diseases. However, the role of ezetimibe in osteoarthritis remains unclear.

Objectives: This study aimed to explore the anti-inflammation effect of ezetimibe on mouse chondrocytes.

Methods: In the present study, ELISA, qPCR and western blot analysis were performed to evaluate the anti-inflammatory effects of ezetimibe. In addition, enzymes that are highly associated with the anabolism and catabolism of the extracellular matrix of the articular cartilage were also evaluated.

Results: Treatment with ezetimibe attenuated the IL-1β-induced degradation of the extracellular matrix, including aggrecan and collagen II. Ezetimibe also attenuated the IL-1β-induced expression levels of MMP3, MMP13 and ADAMTS5, thus exerting protective effects against IL-1β- induced extracellular matrix degradation. The complex mechanism of the anti-inflammatory reaction contributed to the activation of the Nrf2/HO-1 pathway and the suppression of the NF-κB pathway.

Conclusion: On the whole, the present study demonstrates that ezetimibe may be a promising agent for further osteoarthritis therapy.

Keywords: Ezetimibe, osteoarthritis, IL-1β, Nrf2/HO-1, NF-κB, chondrocytes.

« Previous
Graphical Abstract
[1]
Guilak, F.; Nims, R.J.; Dicks, A.; Wu, C-L.; Meulenbelt, I. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol., 2018, 71-72, 40-50.
[http://dx.doi.org/10.1016/j.matbio.2018.05.008] [PMID: 29800616]
[2]
Blanco, F.J.; Rego, I.; Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol., 2011, 7(3), 161-169.
[http://dx.doi.org/10.1038/nrrheum.2010.213] [PMID: 21200395]
[3]
Martin, J.A.; Buckwalter, J.A. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J. Bone Joint Surg. Am., 2003, 85-A(Suppl. 2), 106-110.
[http://dx.doi.org/10.2106/00004623-200300002-00014] [PMID: 12721352]
[4]
Eyre, D.R. Collagens and cartilage matrix homeostasis. Clin. Orthop. Relat. Res., 2004, (427)(Suppl.), S118-S122.
[http://dx.doi.org/10.1097/01.blo.0000144855.48640.b9] [PMID: 15480053]
[5]
Maldonado, M.; Nam, J. The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteo-arthritis. BioMed Res. Int., 2013, 2013, 284873.
[http://dx.doi.org/10.1155/2013/284873] [PMID: 24069595]
[6]
Jovanovic, D.V.; Di Battista, J.A.; Martel-Pelletier, J.; Jolicoeur, F.C.; He, Y.; Zhang, M.; Mineau, F.; Pelletier, J.P. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α by human macrophages. J. Immunol., 1998, 160(7), 3513-3521.
[PMID: 9531313]
[7]
Attur, M.; Al-Mussawir, H.E.; Patel, J.; Kitay, A.; Dave, M.; Palmer, G.; Pillinger, M.H.; Abramson, S.B. Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor. J. Immunol., 2008, 181(7), 5082-5088.
[http://dx.doi.org/10.4049/jimmunol.181.7.5082] [PMID: 18802112]
[8]
Fernandes, J.C.; Martel-Pelletier, J.; Pelletier, J.P. The role of cytokines in osteoarthritis pathophysiology. Biorheology, 2002, 39(1-2), 237-246.
[PMID: 12082286]
[9]
Glasson, S.S.; Askew, R.; Sheppard, B.; Carito, B.; Blanchet, T.; Ma, H-L.; Flannery, C.R.; Peluso, D.; Kanki, K.; Yang, Z.; Majumdar, M.K.; Morris, E.A. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature, 2005, 434(7033), 644-648.
[http://dx.doi.org/10.1038/nature03369] [PMID: 15800624]
[10]
Cai, D.; Yin, S.; Yang, J.; Jiang, Q.; Cao, W. Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Res. Ther., 2015, 17, 269.
[http://dx.doi.org/10.1186/s13075-015-0774-3] [PMID: 26408027]
[11]
Burrage, P.S.; Mix, K.S.; Brinckerhoff, C.E. Matrix metalloproteinases: role in arthritis. Front. Biosci., 2006, 11, 529-543.
[http://dx.doi.org/10.2741/1817] [PMID: 16146751]
[12]
Cannon, C.P.; Blazing, M.A.; Giugliano, R.P.; McCagg, A.; White, J.A.; Theroux, P.; Darius, H.; Lewis, B.S.; Ophuis, T.O.; Jukema, J.W.; De Ferrari, G.M.; Ruzyllo, W.; De Lucca, P. Im, K.; Bohula, E.A.; Reist, C.; Wiviott, S.D.; Tershakovec, A.M.; Musliner, T.A.; Braunwald, E.; Califf, R.M. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med., 2015, 372(25), 2387-2397.
[http://dx.doi.org/10.1056/NEJMoa1410489] [PMID: 26039521]
[13]
Mäki-Petäjä, K.M.; Booth, A.D.; Hall, F.C.; Wallace, S.M.L.; Brown, J.; McEniery, C.M.; Wilkinson, I.B. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J. Am. Coll. Cardiol., 2007, 50(9), 852-858.
[http://dx.doi.org/10.1016/j.jacc.2007.04.076] [PMID: 17719471]
[14]
Yu, J.; Wang, W-n.; Matei, N.; Li, X.; Pang, J-w. Mo, J Ezetimibe attenuates oxidative stress and neuroinflammation via the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Oxid. Med. Cell. Longev., 2020, 2020, 1-14.
[15]
Peserico, D.; Stranieri, C.; Garbin, U.; Mozzini, C. C.; Danese, E.; Cominacini, L.; Fratta Pasini, A.M. Ezetimibe prevents ische-mia/reperfusion-induced oxidative stress and up-regulates Nrf2/ARE and UPR signaling pathways. Antioxidants, 2020, 9(4), 349.
[http://dx.doi.org/10.3390/antiox9040349] [PMID: 32340270]
[16]
Lee, D.H.; Han, D.H.; Nam, K.T.; Park, J.S.; Kim, S.H.; Lee, M.; Kim, G.; Min, B.S.; Cha, B.S.; Lee, Y.S.; Sung, S.H.; Jeong, H.; Ji, H.W.; Lee, M.J.; Lee, J.S.; Lee, H.Y.; Chun, Y.; Kim, J.; Komatsu, M.; Lee, Y.H.; Bae, S.H. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 ac-tivator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radic. Biol. Med., 2016, 99, 520-532.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.09.009] [PMID: 27634173]
[17]
Bellezza, I.; Giambanco, I.; Minelli, A.; Donato, R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta Mol. Cell Res., 2018, 1865(5), 721-733.
[http://dx.doi.org/10.1016/j.bbamcr.2018.02.010] [PMID: 29499228]
[18]
Son, Y.; Lee, J.H.; Chung, H-T.; Pae, H-O. Therapeutic roles of heme oxygenase-1 in metabolic diseases: curcumin and resveratrol ana-logues as possible inducers of heme oxygenase-1. Oxid. Med. Cell. Longev., 2013, 2013, 639541.
[http://dx.doi.org/10.1155/2013/639541]
[19]
Lee, T-S.; Chau, L-Y. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat. Med., 2002, 8(3), 240-246.
[http://dx.doi.org/10.1038/nm0302-240] [PMID: 11875494]
[20]
Khan, N.M.; Haseeb, A.; Ansari, M.Y.; Devarapalli, P.; Haynie, S.; Haqqi, T.M. Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes. Free Radic. Biol. Med., 2017, 106, 288-301.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.02.041] [PMID: 28237856]
[21]
Tang, S.; Tang, Q.; Jin, J.; Zheng, G.; Xu, J.; Huang, W.; Li, X.; Shang, P.; Liu, H. Polydatin inhibits the IL-1β-induced inflammatory re-sponse in human osteoarthritic chondrocytes by activating the Nrf2 signaling pathway and ameliorates murine osteoarthritis. Food Funct., 2018, 9(3), 1701-1712.
[http://dx.doi.org/10.1039/C7FO01555K] [PMID: 29484338]
[22]
Moos, V.; Rudwaleit, M.; Herzog, V.; Höhlig, K.; Sieper, J.; Müller, B. Association of genotypes affecting the expression of interleukin-1β or interleukin-1 receptor antagonist with osteoarthritis. Arthritis Rheum., 2000, 43(11), 2417-2422.
[http://dx.doi.org/10.1002/1529-0131(200011)43:11<2417:AID-ANR7>3.0.CO;2-R] [PMID: 11083263]
[23]
Scanzello, C.R. Chemokines and inflammation in osteoarthritis: Insights from patients and animal models. J. Orthop. Res., 2017, 35(4), 735-739.
[http://dx.doi.org/10.1002/jor.23471] [PMID: 27808445]
[24]
Charlier, E.; Relic, B.; Deroyer, C.; Malaise, O.; Neuville, S.; Collée, J.; Malaise, M.G.; De Seny, D. Insights on molecular mechanisms of chondrocytes death in osteoarthritis. Int. J. Mol. Sci., 2016, 17(12), 17.
[http://dx.doi.org/10.3390/ijms17122146] [PMID: 27999417]
[25]
Wojdasiewicz, P. Poniatowski, ŁA; Szukiewicz, D The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteo-arthritis. Mediators Inflamm., 2014, 2014, 561459.
[http://dx.doi.org/10.1155/2014/561459]
[26]
McInnes, I.B.; Leung, B.P.; Field, M.; Wei, X.Q.; Huang, F-P.; Sturrock, R.D.; Kinninmonth, A.; Weidner, J.; Mumford, R.; Liew, F.Y. Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J. Exp. Med., 1996, 184(4), 1519-1524.
[http://dx.doi.org/10.1084/jem.184.4.1519] [PMID: 8879223]
[27]
Park, J.Y.; Pillinger, M.H.; Abramson, S.B. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin. Immunol., 2006, 119(3), 229-240.
[http://dx.doi.org/10.1016/j.clim.2006.01.016] [PMID: 16540375]
[28]
Li, N.; Rivéra-Bermúdez, M.A.; Zhang, M.; Tejada, J.; Glasson, S.S.; Collins-Racie, L.A.; Lavallie, E.R.; Wang, Y.; Chang, K.C.; Nagpal, S.; Morris, E.A.; Flannery, C.R.; Yang, Z. LXR modulation blocks prostaglandin E2 production and matrix degradation in cartilage and al-leviates pain in a rat osteoarthritis model. Proc. Natl. Acad. Sci. USA, 2010, 107(8), 3734-3739.
[http://dx.doi.org/10.1073/pnas.0911377107] [PMID: 20133709]
[29]
Boehme, K.A.; Rolauffs, B. Onset and progression of human osteoarthritis-can growth factors, inflammatory cytokines, or differential miRNA expression concomitantly induce proliferation, ECM degradation, and inflammation in articular cartilage? Int. J. Mol. Sci., 2018, 19(8), 2282.
[http://dx.doi.org/10.3390/ijms19082282] [PMID: 30081513]
[30]
Malemud, CJ Matrix metalloproteinases (MMPs) in health and disease: an overview. Front. Biosci., 2006, 11, 1696-1701.
[31]
Kelwick, R.; Desanlis, I.; Wheeler, G.N.; Edwards, D.R. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin mo-tifs) family. Genome Biol., 2015, 16, 113.
[http://dx.doi.org/10.1186/s13059-015-0676-3] [PMID: 26025392]
[32]
Cuadrado, A.; Rojo, A.I.; Wells, G.; Hayes, J.D.; Cousin, S.P.; Rumsey, W.L.; Attucks, O.C.; Franklin, S.; Levonen, A.L.; Kensler, T.W.; Dinkova-Kostova, A.T. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov., 2019, 18(4), 295-317.
[http://dx.doi.org/10.1038/s41573-018-0008-x] [PMID: 30610225]
[33]
Subedi, L.; Lee, J.H.; Yumnam, S.; Ji, E.; Kim, S.Y. Anti-inflammatory effect of sulforaphane on LPS-activated microglia potentially through JNK/AP-1/NF-κB inhibition and Nrf2/HO-1 activation. Cells, 2019, 8(2), 194.
[http://dx.doi.org/10.3390/cells8020194] [PMID: 30813369]
[34]
Cho, H-Y.; Reddy, S.P.; Kleeberger, S.R. Nrf2 defends the lung from oxidative stress. Antioxid. Redox Signal., 2006, 8(1-2), 76-87.
[http://dx.doi.org/10.1089/ars.2006.8.76] [PMID: 16487040]
[35]
Loboda, A.; Damulewicz, M.; Pyza, E.; Jozkowicz, A.; Dulak, J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell. Mol. Life Sci., 2016, 73(17), 3221-3247.
[http://dx.doi.org/10.1007/s00018-016-2223-0] [PMID: 27100828]
[36]
Park, C.; Hong, S.H.; Shin, S.S.; Lee, D-S.; Han, M.H.; Cha, H-J.; Kim, S.; Kim, H.S.; Kim, G.Y.; Park, E.K.; Jeon, Y.J.; Choi, Y.H. Activa-tion of the Nrf2/HO-1 signaling pathway contributes to the protective effects of Sargassum serratifolium extract against oxidative stress-induced DNA damage and apoptosis in SW1353 human chondrocytes. Int. J. Environ. Res. Public Health, 2018, 15(6), 1173.
[http://dx.doi.org/10.3390/ijerph15061173] [PMID: 29874784]
[37]
Wang, Y.; Chen, Y.; Chen, Y.; Zhou, B.; Shan, X.; Yang, G. Eriodictyol inhibits IL-1β-induced inflammatory response in human osteoar-thritis chondrocytes. Biomed. Pharmacother., 2018, 107, 1128-1134.
[http://dx.doi.org/10.1016/j.biopha.2018.08.103] [PMID: 30257325]
[38]
Brasier, A.R. The NF-kappaB regulatory network. Cardiovasc. Toxicol., 2006, 6(2), 111-130.
[http://dx.doi.org/10.1385/CT:6:2:111] [PMID: 17303919]
[39]
Bellezza, I.; Mierla, A.L.; Minelli, A. Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancers (Basel), 2010, 2(2), 483-497.
[http://dx.doi.org/10.3390/cancers2020483] [PMID: 24281078]
[40]
Marcu, K. B.; Otero, M.; Olivotto, E.; Maria, Borzi R.; Goldring M., B. NF-κB signaling: multiple angles to target OA. Curr. Drug Targets, 2010, 11, 599-613.
[http://dx.doi.org/10.2174/138945010791011938]
[41]
Hayden, M.S.; Ghosh, S. Regulation of NF-κB by TNF family cytokines, , 3rd ed; 253-266.
[42]
Tian, Y.; Yuan, W.; Fujita, N.; Wang, J.; Wang, H.; Shapiro, I.M.; Risbud, M.V. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-&#954. B. Am. J. Pathol., 2013, 182(6), 2310-2321.
[http://dx.doi.org/10.1016/j.ajpath.2013.02.037] [PMID: 23602832]
[43]
Kobayashi, H.; Hirata, M.; Saito, T.; Itoh, S.; Chung, U.I.; Kawaguchi, H. Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development. J. Biol. Chem., 2013, 288(40), 28620-28629.
[http://dx.doi.org/10.1074/jbc.M113.452169] [PMID: 23963448]
[44]
Carrero, R.; Cerrada, I.; Lledó, E.; Dopazo, J.; García-García, F.; Rubio, M-P.; Trigueros, C.; Dorronsoro, A.; Ruiz-Sauri, A.; Montero, J.A.; Sepúlveda, P. IL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-&#954. B. Stem Cell Rev. Rep., 2012, 8(3), 905-916.
[http://dx.doi.org/10.1007/s12015-012-9364-9] [PMID: 22467443]
[45]
de Lange-Brokaar, B.J.E.; Ioan-Facsinay, A.; van Osch, G.J.V.M.; Zuurmond, A.M.; Schoones, J.; Toes, R.E.M.; Huizinga, T.W.; Klop-penburg, M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage, 2012, 20(12), 1484-1499.
[http://dx.doi.org/10.1016/j.joca.2012.08.027] [PMID: 22960092]
[46]
Suchy, D. Łabuzek, K.; Machnik, G.; Okopień, B. The influence of ezetimibe on classical and alternative activation pathways of monocytes/macrophages isolated from patients with hypercholesterolemia. Naunyn Schmiedebergs Arch. Pharmacol., 2014, 387(8), 733-742.
[http://dx.doi.org/10.1007/s00210-014-0982-4] [PMID: 24781446]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy