Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast‑like synoviocytes

Li,Yu; Xing,Qunzhi; Wei,Yuanzhang; Zhao,Lei; Zhang,Pei; Han,Xuechang; Wang,Jing

doi:10.3892/ijmm.2019.4336

Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast‑like synoviocytes

Authors:
- Yu Li
- Qunzhi Xing
- Yuanzhang Wei
- Lei Zhao
- Pei Zhang
- Xuechang Han
- Jing Wang
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Affiliations: Ache Department, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Anesthesiology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
Published online on: September 10, 2019 https://doi.org/10.3892/ijmm.2019.4336
Pages: 1963-1970

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Abstract

Rheumatoid arthritis (RA) is a debilitating joint disease characterized by chronic inflammation, pathologic alteration of fibroblast‑like synoviocytes (FLS), destruction of cartilage and bone, and the formation of an invasive pannus. RA‑FLS exhibit increased proliferation and resistance to apoptosis. The retinoid X receptor (RXR) has a role in regulating cell cycle, differentiation and apoptosis, and agonism of RXR has been investigated as a treatment strategy in several types of cancer. However, there is little research on the effects of RXR agonism in other diseases. Bexarotene is a novel selective RXR ligand used in the treatment of T‑cell lymphoma. In the present study, bexarotene was used to investigate the involvement of RXR in tumor necrosis factor‑α (TNF‑α)‑induced RA conditions in human FLS. To the best of our knowledge, this is the first time that RXR has been demonstrated to be expressed in FLS and to be downregulated in response to TNF‑α stimulation. The present study also demonstrated that bexarotene exerted an anti‑inflammatory effect by downregulating expression of interleukin (IL)‑6, IL‑8, monocyte chemoattractant protein‑1, and high mobility group box‑1. Notably, bexarotene also rescued the TNF‑α‑induced downregulation of the anti‑inflammatory cytokines IL‑4 and transforming growth factor‑β1. Bexarotene treatment exhibited a potential protective effect against cartilage degradation by downregulating the expression of matrix metalloproteinase (MMP)‑1, MMP‑3 and MMP‑13. In addition, the present results demonstrated that the effects of bexarotene were mediated through the p38 mitogen‑activated protein kinase/nuclear factor‑κB pathway, via inhibition of p38 protein and the inhibitor α of κB phosphorylation. Taken together, the present findings demonstrated the potential of RXR agonism using bexarotene as a treatment against the development and progression of RA.

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1	Sweeney SE and Firestein GS: Rheumatoid arthritis: Regulation of synovial inflammation. Int J Biochem Cell Biol. 36:372–378. 2004. View Article : Google Scholar
2	Pap T and Korb-Pap A: Cartilage damage in osteoarthritis and rheumatoid arthritis-two unequal siblings. Nat Rev Rheumatol. 11:606–615. 2015. View Article : Google Scholar : PubMed/NCBI
3	Bresnihan B: Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 26:717–719. 1999.PubMed/NCBI
4	Bartok B and Firestein GS: Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol Rev. 233:233–255. 2010. View Article : Google Scholar : PubMed/NCBI
5	Nanki T, Nagasaka K, Hayashida K, Saita Y and Miyasaka N: Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol. 167:5381–5385. 2001. View Article : Google Scholar : PubMed/NCBI
6	Georganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B and Pope RM: Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: The dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol. 165:7199–7206. 2000. View Article : Google Scholar : PubMed/NCBI
7	Yokota K, Miyazaki T, Hirano M, Akiyama Y and Mimura T: Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Rheumatol. 33:463–471. 2006.PubMed/NCBI
8	Harigai M, Hara M, Yoshimura T, Leonard EJ, Inoue K and Kashiwazaki S: Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol. 69:83–91. 1993. View Article : Google Scholar : PubMed/NCBI
9	Green MJ, Gough AK, Devlin J, Smith J, Astin P, Taylor D and Emery P: Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology (Oxford). 42:83–88. 2003. View Article : Google Scholar
10	Agere SA, Akhtar N, Watson JM and Ahmed S: RANTES/CCL5 induces collagen degradation by activating MMP-1 and MMP-13 expression in human rheumatoid arthritis synovial fibroblasts. Front Immunol. 8:13412017. View Article : Google Scholar : PubMed/NCBI
11	Lubberts E, Joosten LA, Chabaud M, van den Bersselaar L, Oppers B, Coenen-de Roo CJ, Richards CD, Miossec P and van den Berg WB: IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. J Clin Invest. 105:1697–1710. 2000. View Article : Google Scholar : PubMed/NCBI
12	Chemel M, Brion R, Segaliny A, Lamora A, Charrier C, Brulin B, Maugars Y, Le Goff B, Heymann D and Verrecchia F: Bone morphogenetic protein 2 and transforming growth factor-β1 inhibit the expression of the pro-inflammatory cytokine IL-34 in rheumatoid arthritis synovial fibroblasts. Am J Pathol. 187:156–162. 2017. View Article : Google Scholar
13	Sugiura Y, Niimi T, Sato S, Yoshinouchi T, Banno S, Naniwa T, Maeda H, Shimizu S and Ueda R: Transforming growth factor β1 gene polymorphism in rheumatoid arthritis. Ann Rheum Dis. 61:826–828. 2002. View Article : Google Scholar : PubMed/NCBI
14	Mateen S, Zafar A, Moin S, Khan AQ and Zubair S: Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 455:161–171. 2016. View Article : Google Scholar : PubMed/NCBI
15	Kageyama Y, Takahashi M, Ichikawa T, Torikai E and Nagano A: Reduction of oxidative stress marker levels by anti-TNF-alpha antibody, infliximab, in patients with rheumatoid arthritis. Clin Exp Rheumatol. 26:73–80. 2008.PubMed/NCBI
16	Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, Breedveld FC, Smolen JS, Eberl G, deWoody K, et al: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 163:1521–1528. 1999.PubMed/NCBI
17	Gottenberg JE, Brocq O, Perdriger A, Lassoued S, Berthelot JM, Wendling D, Euller-Ziegler L, Soubrier M, Richez C, Fautrel B, et al: Non-TNF-targeted biologic vs. a second anti-TNF drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: A randomized clinical trial. JAMA. 316:1172–1180. 2016. View Article : Google Scholar : PubMed/NCBI
18	Li L, Liu Y, Wang J, Chen L, Zhang W and Yan X: Preparation, in vitro and in vivo evaluation of bexarotene nanocrystals with surface modification by folate-chitosan conjugates. Drug Deliv. 23:79–87. 2016. View Article : Google Scholar
19	Yen WC, Prudente RY, Corpuz MR, Negro-Vilar A and Lamph WW: A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. Br J Cancer. 94:654–660. 2006. View Article : Google Scholar : PubMed/NCBI
20	Yamanishi Y, Boyle DL, Green DR, Keystone EC, Connor A, Zollman S and Firestein GS: P53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis. Arthritis Res Ther. 7:R12–R18. 2005. View Article : Google Scholar : PubMed/NCBI
21	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. View Article : Google Scholar
22	Terraneo L, Bianciardi P, Malavalli A, Mkrtchyan G, Spann SN, Lohman J, Samaja M and Vandegriff KD: Hemoglobin extravasation in the brain of rats exchange-transfused with hemoglobin-based oxygen carriers. Artif Cells Nanomed Biotechnol. 45:710–716. 2017. View Article : Google Scholar
23	Ma S, Bai Z, Wu H and Wang W: The DPP-4 inhibitor saxagliptin ameliorates ox-LDL-induced endothelial dysfunction by regulating AP-1 and NF-κB. Eur J Pharmacol. 851:186–193. 2019. View Article : Google Scholar : PubMed/NCBI
24	Schett G, Zwerina J and Firestein G: The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis. 67:909–916. 2008. View Article : Google Scholar
25	Mitchell JP and Carmody RJ: NF-κB and the transcriptional control of inflammation. Int Rev Cell Mol Biol. 335:41–84. 2018. View Article : Google Scholar
26	Noack M and Miossec P: Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol. 39:365–383. 2017. View Article : Google Scholar : PubMed/NCBI
27	Emdad L, Das SK, Hu B, Kegelman T, Kang DC, Lee SG, Sarkar D and Fisher PB: AEG-1/MTDH/LYRIC: A promiscuous protein partner critical in cancer, obesity, and CNS diseases. Adv Cancer Res. 131:97–132. 2016. View Article : Google Scholar : PubMed/NCBI
28	Chiazza F and Collino M: Peroxisome proliferator-activated receptors (PPARs) in glucose control. Mol Nutri Diabetes. 105–114. 2016. View Article : Google Scholar
29	Vincenti MP, Clark IM and Brinckerhoff CE: Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? Arthritis Rheum. 37:1115–1126. 1994.
30	Mosquera N, Rodriguez-Trillo A, Mera-Varela A, Gonzalez A and Conde C: Uncovering Cellular retinoic acid-binding protein 2 as a potential target for rheumatoid arthritis synovial hyper-plasia. Sci Rep. 8:87312018. View Article : Google Scholar
31	Uray IP and Brown PH: Chemoprevention of hormone receptor-negative breast cancer: New approaches needed. Recent Results Cancer Res. 188:147–162. 2011. View Article : Google Scholar : PubMed/NCBI
32	Zhang D, Leal AS, Carapellucci S, Zydeck K, Chaaban N, Sporn MB, Wagner CE and Liby KT: Comparison of the rexinoids Bexarotene and Pyrimidine-Bexarotene in a preclinical model of lung carcinogenesis. FASEB J. 31(Suppl 1): S671–S616. 2017.
33	Zhong J, Cheng C, Liu H, Huang Z, Wu Y, Teng Z, He J, Zhang H, Wu J, Cao F, et al: Bexarotene protects against traumatic brain injury in mice partially through apolipoprotein E. Neuroscience. 343:434–448. 2017. View Article : Google Scholar
34	Tunctan B, Kucukkavruk SP, Temiz-Resitoglu M, Guden DS, Sari AN and Sahan-Firat S: Bexarotene, a selective RXRα agonist, reverses hypotension associated with inflammation and tissue injury in a rat model of septic shock. Inflammation. 41:337–355. 2018. View Article : Google Scholar
35	Kim DH, Lee GC, Kim CH, Oh SW, Han KH and Han SY: Anti-inflammatory effect of combination therapy with rosiglitazone and all-trans retinoic acid on high glucose-induced MCP-1 response in rat mesangial cells. Biomed Res. 28:463–467. 2017.
36	Escudero P, Martinez de Marañón A, Collado A, Gonzalez- Navarro H, Hermenegildo C, Peiró C, Piqueras L and Sanz MJ: Combined sub-optimal doses of rosuvastatin and bexarotene impair angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions. Antioxid Redox Signal. 22:901–920. 2015. View Article : Google Scholar : PubMed/NCBI
37	Li Z, Niu X, Xiao S and Ma H: Retinoic acid ameliorates photo-aged skin through RAR-mediated pathway in mice. Mol Med Rep. 16:6240–6247. 2017. View Article : Google Scholar : PubMed/NCBI
38	Westra J and Limburg PC: p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini Rev Med Chem. 6:867–874. 2006. View Article : Google Scholar : PubMed/NCBI
39	Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, et al: Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer: A basis for new therapeutic strategies. J Exp Med. 193:827–838. 2001. View Article : Google Scholar : PubMed/NCBI
40	Fan Y, Wang J, Wei L, He B, Wang C and Wang B: Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-κB pathway. Int J Cardiol. 152:49–55. 2011. View Article : Google Scholar