Generic placeholder image

Current Pharmaceutical Biotechnology

Author(s): Chenzhe Ni, Wanglin Zhang, Sai Qiu*, Hao Cheng* and Chunhui Ma*

DOI: 10.2174/0113892010275579240116061104

DownloadDownload PDF Flyer Cite As
Long Non-coding RNA DLEU1 Promotes Progression of Osteoarthritis via miR-492/TLR8 Axis

Page: [2166 - 2181] Pages: 16

  • * (Excluding Mailing and Handling)

Abstract

Background: Long non-coding RNAs (LncRNAs) are generally reported to participate in the development of Osteoarthritis (OA) by acting as competing endogenous RNAs (ceRNAs). However, the molecular mechanism is largely unknown. This study aimed to investigate the possible mechanisms contributing to osteoarthritis (OA).

Methods: Four gene expression profiles from patients with OA were downloaded from a public database and integrated to screen important RNAs associated with OA. Differentially expressed (DE) lncRNAs, microRNAs (miRNAs), and mRNAs were filtered, and a ceRNA network was constructed. An in vitro OA model was established by treating chondrocytes with IL-1β. The expression levels of MMP-13, COL2A1, aggrecan, and RUNX2 were detected by qRT-PCR and western blot. Cell proliferation ability was detected by CCK-8 assay. Flow cytometry was used for apoptosis assay. A dual luciferase reporter gene was used to confirm the relationship between DLEU1, miR-492, and TLR8.

Results: An OA-related ceRNA network, including 11 pathways, 3 miRNAs, 7 lncRNAs, and 16 mRNAs, was constructed. DLEU1 and TLR8 were upregulated, and miR-492 was downregulated in IL-1β-induced chondrocytes. Overexpression of DLEU1 suppressed viability and promoted apoptosis and extracellular matrix (ECM) degradation in IL-1β induced chondrocytes. Luciferase reporter assay validated the regulatory relations among DLEU1, miR-492, and TLR8. Further study revealed that the effects of DLEU1 on chondrocytes could be reversed by miR-492.

Conclusion: DLEU1 may be responsible for the viability, apoptosis, and ECM degradation in OA via miR-492/TLR8 axis.

Graphical Abstract

[1]
Allen, K.D.; Choong, P.F.; Davis, A.M.; Dowsey, M.M.; Dziedzic, K.S.; Emery, C.; Hunter, D.J.; Losina, E.; Page, A.E.; Roos, E.M.; Skou, S.T.; Thorstensson, C.A.; van der Esch, M.; Whittaker, J.L. Osteoarthritis: Models for appropriate care across the disease continuum. Best Pract. Res. Clin. Rheumatol., 2016, 30(3), 503-535.
[http://dx.doi.org/10.1016/j.berh.2016.09.003] [PMID: 27886944]
[2]
Poole, A.R. Osteoarthritis as a whole joint disease. HSS J., 2012, 8(1), 4-6.
[http://dx.doi.org/10.1007/s11420-011-9248-6] [PMID: 23372516]
[3]
Allen, K.D.; Thoma, L.M.; Golightly, Y.M. Epidemiology of osteoarthritis. Osteoarthritis Cartilage, 2022, 30(2), 184-195.
[http://dx.doi.org/10.1016/j.joca.2021.04.020] [PMID: 34534661]
[4]
Foster, N.E.; Eriksson, L.; Deveza, L.; Hall, M. Osteoarthritis year in review 2022: Epidemiology & therapy. Osteoarthritis Cartilage, 2023, 31(7), 876-883.
[http://dx.doi.org/10.1016/j.joca.2023.03.008] [PMID: 36963607]
[5]
Yao, Q.; Wu, X.; Tao, C.; Gong, W.; Chen, M.; Qu, M.; Zhong, Y.; He, T.; Chen, S.; Xiao, G. Osteoarthritis: Pathogenic signaling pathways and therapeutic targets. Signal Transduct. Target. Ther., 2023, 8(1), 56.
[http://dx.doi.org/10.1038/s41392-023-01330-w] [PMID: 36737426]
[6]
Giorgino, R.; Albano, D.; Fusco, S.; Peretti, G.M.; Mangiavini, L.; Messina, C. Knee osteoarthritis: Epidemiology, pathogenesis, and mesenchymal stem cells: What else is new? an update. Int. J. Mol. Sci., 2023, 24(7), 6405.
[http://dx.doi.org/10.3390/ijms24076405] [PMID: 37047377]
[7]
Majeed, MH; Sherazi, SAA; Bacon, D; Bajwa, ZH Pharmacological treatment of pain in osteoarthritis: A descriptive review., Curr Rheumatol Rep., 2018, 20(12), 018-0794.
[http://dx.doi.org/10.1007/s11926-018-0794-5]
[8]
Carlson, V.R.; Ong, A.C.; Orozco, F.R.; Hernandez, V.H.; Lutz, R.W.; Post, Z.D. Compliance with the AAOS guidelines for treatment of osteoarthritis of the knee: A survey of the American association of hip and knee surgeons. J. Am. Acad. Orthop. Surg., 2018, 26(3), 103-107.
[http://dx.doi.org/10.5435/JAAOS-D-17-00164] [PMID: 29283898]
[9]
Smith, M.D. The normal synovium. Open Rheumatol. J., 2011, 5, 100-106.
[http://dx.doi.org/10.2174/1874312901105010100] [PMID: 22279508]
[10]
Bondeson, J.; Blom, A.B.; Wainwright, S.; Hughes, C.; Caterson, B.; van den Berg, W.B. The role of synovial macrophages and macrophage‐produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum., 2010, 62(3), 647-657.
[http://dx.doi.org/10.1002/art.27290] [PMID: 20187160]
[11]
Pettenuzzo, S.; Arduino, A.; Belluzzi, E.; Pozzuoli, A.; Fontanella, C.G.; Ruggieri, P.; Salomoni, V.; Majorana, C.; Berardo, A. Biomechanics of chondrocytes and chondrons in healthy conditions and osteoarthritis: A review of the mechanical characterisations at the microscale. Biomedicines, 2023, 11(7), 1942.
[http://dx.doi.org/10.3390/biomedicines11071942] [PMID: 37509581]
[12]
Belluzzi, E.; Todros, S.; Pozzuoli, A.; Ruggieri, P.; Carniel, E.L.; Berardo, A. Human cartilage biomechanics: Experimental and theoretical approaches towards the identification of mechanical properties in healthy and osteoarthritic conditions. Processes, 2023, 11(4), 1014.
[http://dx.doi.org/10.3390/pr11041014]
[13]
Emmi, A.; Stocco, E.; Boscolo-Berto, R.; Contran, M.; Belluzzi, E.; Favero, M.; Ramonda, R.; Porzionato, A.; Ruggieri, P.; De Caro, R.; Macchi, V. Infrapatellar fat pad-synovial membrane anatomo-fuctional unit: Microscopic basis for piezo1/2 mechanosensors involvement in osteoarthritis pain. Front. Cell Dev. Biol., 2022, 10, 886604.
[http://dx.doi.org/10.3389/fcell.2022.886604] [PMID: 35837327]
[14]
Krawetz, R.J.; Wu, Y.E.; Bertram, K.L.; Shonak, A.; Masson, A.O.; Ren, G.; Leonard, C.; Kapoor, M.; Matyas, J.R.; Salo, P.T. Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity. Cell Death Dis., 2022, 13(5), 470.
[http://dx.doi.org/10.1038/s41419-022-04919-1] [PMID: 35585042]
[15]
Lai, C.; Liao, B.; Peng, S.; Fang, P.; Bao, N.; Zhang, L. Synovial fibroblast-miR-214-3p-derived exosomes inhibit inflammation and degeneration of cartilage tissues of osteoarthritis rats. Mol. Cell. Biochem., 2023, 478(3), 637-649.
[http://dx.doi.org/10.1007/s11010-022-04535-9] [PMID: 36001206]
[16]
Wang, L.; Cho, K.B.; Li, Y.; Tao, G.; Xie, Z.; Guo, B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int. J. Mol. Sci., 2019, 20(22), 5758.
[http://dx.doi.org/10.3390/ijms20225758] [PMID: 31744051]
[17]
Hu, J; Wang, Z; Shan, Y; Pan, Y; Ma, J; Jia, L. Long non-coding RNA HOTAIR promotes osteoarthritis progression via miR-17-5p/FUT2/β- catenin axis. Cell Death Dis., 2018, 9(7), 018-0746.
[18]
Li, Y.; Li, S.; Luo, Y.; Liu, Y.; Yu, N. LncRNA PVT1 regulates chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR-488-3p. DNA Cell Biol., 2017, 36(7), 571-580.
[http://dx.doi.org/10.1089/dna.2017.3678] [PMID: 28520497]
[19]
Du, Z.; Sun, T.; Hacisuleyman, E.; Fei, T.; Wang, X.; Brown, M.; Rinn, J.L.; Lee, M.G.S.; Chen, Y.; Kantoff, P.W.; Liu, X.S. Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat. Commun., 2016, 7(1), 10982.
[http://dx.doi.org/10.1038/ncomms10982] [PMID: 26975529]
[20]
Karreth, FA; Reschke, M; Ruocco, A; Ng, C; Chapuy, B; Léopold, V; Sjoberg, M; Keane, TM; Verma, A; Ala, U; Tay, Y; Wu, D; Seitzer, N The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. cell, 2015, 161(2), 319-332.
[21]
Liu, N.; Huang, Y.; Shao, Y.; Fan, X.; Sun, H.; Wang, T.; Yao, T.; Chen, X.Y. The regulatory role and mechanism of lncTUG1 on cartilage apoptosis and inflammation in osteoarthritis. Arthritis Res. Ther., 2023, 25(1), 106.
[http://dx.doi.org/10.1186/s13075-023-03087-7] [PMID: 37340458]
[22]
Barrett, T.; Wilhite, S.E.; Ledoux, P.; Evangelista, C.; Kim, I.F.; Tomashevsky, M.; Marshall, K.A.; Phillippy, K.H.; Sherman, P.M.; Holko, M.; Yefanov, A.; Lee, H.; Zhang, N.; Robertson, C.L.; Serova, N.; Davis, S.; Soboleva, A. NCBI GEO: Archive for functional genomics data sets--update. Nucleic Acids Res., 2013, 41(Database issue), D991-D995.
[PMID: 23193258]
[23]
Wang, X.; Kang, D.D.; Shen, K.; Song, C.; Lu, S.; Chang, L.C.; Liao, S.G.; Huo, Z.; Tang, S.; Ding, Y.; Kaminski, N.; Sibille, E.; Lin, Y.; Li, J.; Tseng, G.C. An R package suite for microarray meta-analysis in quality control, differentially expressed gene analysis and pathway enrichment detection. Bioinformatics, 2012, 28(19), 2534-2536.
[http://dx.doi.org/10.1093/bioinformatics/bts485] [PMID: 22863766]
[24]
Langfelder, P.; Horvath, S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics, 2008, 9(1), 559.
[http://dx.doi.org/10.1186/1471-2105-9-559] [PMID: 19114008]
[25]
Paraskevopoulou, M.D.; Vlachos, I.S.; Karagkouni, D.; Georgakilas, G.; Kanellos, I.; Vergoulis, T.; Zagganas, K.; Tsanakas, P.; Floros, E.; Dalamagas, T.; Hatzigeorgiou, A.G. DIANA-LncBase v2: Indexing microRNA targets on non-coding transcripts. Nucleic Acids Res., 2016, 44(D1), D231-D238.
[http://dx.doi.org/10.1093/nar/gkv1270] [PMID: 26612864]
[26]
Li, J.H.; Liu, S.; Zhou, H.; Qu, L.H.; Yang, J.H. starBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res., 2014, 42(D1), D92-D97.
[http://dx.doi.org/10.1093/nar/gkt1248] [PMID: 24297251]
[27]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[28]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[29]
Davis, A.P.; Wiegers, T.C.; Johnson, R.J.; Sciaky, D.; Wiegers, J.; Mattingly, C.J. Comparative Toxicogenomics Database (CTD): Update 2023. Nucleic Acids Res., 2023, 51(D1), D1257-D1262.
[http://dx.doi.org/10.1093/nar/gkac833] [PMID: 36169237]
[30]
Sanchez-Lopez, E.; Coras, R.; Torres, A.; Lane, N.E.; Guma, M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol., 2022, 18(5), 258-275.
[http://dx.doi.org/10.1038/s41584-022-00749-9] [PMID: 35165404]
[31]
Kanthawang, T.; Bodden, J.; Joseph, G.B.; Lane, N.E.; Nevitt, M.; McCulloch, C.E.; Link, T.M. Obese and overweight individuals have greater knee synovial inflammation and associated structural and cartilage compositional degeneration: Data from the osteoarthritis initiative. Skeletal Radiol., 2021, 50(1), 217-229.
[http://dx.doi.org/10.1007/s00256-020-03550-5] [PMID: 32699956]
[32]
Tay, Y.; Rinn, J.; Pandolfi, P.P. The multilayered complexity of ceRNA crosstalk and competition. Nature, 2014, 505(7483), 344-352.
[http://dx.doi.org/10.1038/nature12986] [PMID: 24429633]
[33]
Liu, T.; Han, Z.; Li, H.; Zhu, Y.; Sun, Z.; Zhu, A. LncRNA DLEU1 contributes to colorectal cancer progression via activation of KPNA3. Mol Cancer, 2018, 17(1), 018-0873.
[http://dx.doi.org/10.1186/s12943-018-0873-2]
[34]
Feng, L.; He, M.; Rao, M.; Diao, J.; Zhu, Y. Long noncoding RNA DLEU1 aggravates glioma progression via the miR-421/MEF2D axis. OncoTargets Ther., 2019, 12, 5405-5414.
[http://dx.doi.org/10.2147/OTT.S207542] [PMID: 31360066]
[35]
Li, Q.; Zhang, Z.; Jiang, H.; Hou, J.; Chai, Y.; Nan, H.; Li, F.; Wang, L. DLEU1 promotes cell survival by preventing DYNLL1 degradation in esophageal squamous cell carcinoma. J. Transl. Med., 2022, 20(1), 245.
[http://dx.doi.org/10.1186/s12967-022-03449-w] [PMID: 35619131]
[36]
Hatanaka, Y.; Niinuma, T.; Kitajima, H.; Nishiyama, K.; Maruyama, R.; Ishiguro, K.; Toyota, M.; Yamamoto, E.; Kai, M.; Yorozu, A.; Sekiguchi, S.; Ogi, K.; Dehari, H.; Idogawa, M.; Sasaki, Y.; Tokino, T.; Miyazaki, A.; Suzuki, H. DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes. Sci. Rep., 2021, 11(1), 20438.
[http://dx.doi.org/10.1038/s41598-021-99736-5] [PMID: 34650128]
[37]
Ma, H.N.; Chen, H.J.; Liu, J.Q.; Li, W.T. Long non-coding RNA DLEU1 promotes malignancy of breast cancer by acting as an indispensable coactivator for HIF-1α-induced transcription of CKAP2. Cell Death Dis., 2022, 13(7), 625.
[http://dx.doi.org/10.1038/s41419-022-04880-z] [PMID: 35853854]
[38]
Wu, X.; Yin, S.; Yan, L.; Liu, Y.; Shang, L.; Liu, J. lncRNA DLEU1 modulates proliferation, inflammation, and extracellular matrix degradation of chondrocytes through regulating miR-671-5p. J. Immunol. Res., 2022, 2022, 1-12.
[http://dx.doi.org/10.1155/2022/1816217] [PMID: 35647200]
[39]
Wang, Y.; Chen, L.Y.; Liu-Bryan, R. Mitochondrial biogenesis, activity, and DNA isolation in chondrocytes. Methods Mol. Biol., 2021, 2245, 195-213.
[http://dx.doi.org/10.1007/978-1-0716-1119-7_14] [PMID: 33315204]
[40]
Barreto, G.; Manninen, M.; K Eklund, K. Osteoarthritis and toll-like receptors: When innate immunity meets chondrocyte apoptosis. Biology, 2020, 9(4), 65.
[http://dx.doi.org/10.3390/biology9040065] [PMID: 32235418]
[41]
Li, Y.; Nie, J.; Deng, C.; Li, H. P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis. J. Orthop. Surg. Res., 2023, 18(1), 199.
[http://dx.doi.org/10.1186/s13018-023-03658-z] [PMID: 36915153]
[42]
Okada, A.; Okada, Y. Progress of research in osteoarthritis. Metalloproteinases in osteoarthritis. Clin. Calcium, 2009, 19(11), 1593-1601.
[PMID: 19880991]
[43]
Matyas, J.R.; Adams, M.E.; Huang, D.; Sandell, L.J. Discoordinate gene expression of aggrecan and type ii collagen in experimental osteoarthritis. Arthritis Rheum., 1995, 38(3), 420-425.
[http://dx.doi.org/10.1002/art.1780380320] [PMID: 7533495]
[44]
Long, F. Building strong bones: Molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol., 2012, 13(1), 27-38.
[http://dx.doi.org/10.1038/nrm3254] [PMID: 22189423]
[45]
Chang, S.M.; Hu, W.W. Long non‐coding RNA MALAT1 promotes oral squamous cell carcinoma development via microRNA‐125b/STAT3 axis. J. Cell. Physiol., 2018, 233(4), 3384-3396.
[http://dx.doi.org/10.1002/jcp.26185] [PMID: 28926115]
[46]
Broz, P.; Monack, D.M. Newly described pattern recognition receptors team up against intracellular pathogens. Nat. Rev. Immunol., 2013, 13(8), 551-565.
[http://dx.doi.org/10.1038/nri3479] [PMID: 23846113]
[47]
Miller, R.E.; Scanzello, C.R.; Malfait, A-M. An emerging role for Toll-like receptors at the neuroimmune interface in osteoarthritis. In: Seminars in Immunopathology; Springer, 2019; pp. 583-594.