Generic placeholder image

Current Gene Therapy

Author(s): Mingmin Shi*, Menghao Sun, Cong Wang, Yue Shen, Yangxin Wang and Shigui Yan*

DOI: 10.2174/1566523222666220309150722

DownloadDownload PDF Flyer Cite As
Therapeutic Potential of POU3F3, a Novel Long Non-coding RNA, Alleviates the Pathogenesis of Osteoarthritis by Regulating the miR-29a- 3p/FOXO3 Axis

Page: [427 - 438] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Osteoarthritis (OA) is the predominant threat to the health of the elderly, and it is crucial to understand the molecular pathogenetic mechanisms involved in it. This study aims to investigate the role of a well-studied cancer-related long non-coding RNA (lncRNA)-POU3F3 in OA and its implicated molecular mechanisms.

Methods: The expression of POU3F3 and miR-29a-3p was examined in osteoarthritis patients, as well as destabilization of the medial meniscus (DMM) mouse OA model and IL- 1β induced chondrocytes cell OA model, by quantitative real-time PCR. The interaction between POU3F3, miR-29a-3p and transcription factor forkhead box O3 (FOXO3) was verified via dual-luciferase reporter analysis and RNA immunoprecipitation analyses. Cell proliferation and apoptosis were evaluated by cell viability assay and flow cytometry, respectively. Cartilage extracellular matrix (ECM) degradation was investigated with ELISA and western blotting. In addition, the in vivo regulation of POU3F3 in OA was verified by intra-articular injection of lentivirus overexpression POU3F31 in mice models.

Results: The expression level of POU3F3 was decreased in OA patients/animal cartilage tissues and IL-1β-stimulated in vitro chondrocyte model. POU3F3 overexpression inhibited IL-1β-induced injury of chondrocytes, enhancing cell viability, suppressing apoptosis and inflammatory cytokine secretion, rescuing metabolic dysfunction, and restraining autophagy in vitro. Mechanistically, Luciferase reporter and RNA immunoprecipitation (RIP) assays indicated that miR-29a-3p could directly bind to POU3F3, and FOXO3 was a target gene of miR-29a-3p. Functional rescue assays confirmed this POU3F3/miR-29a-3p/FOXO3 axis in chondrocytes during OA occurrence. Furthermore, intraarticularly delivery of lentivirus containing POU3F3 alleviates the damage in mouse OA model in vivo.

Conclusion: In conclusion, this work highlights the role of the POU3F3/miR-29a-3p/FOXO3 axis in the OA pathogenesis, suggesting this axis as a potential therapeutic target for OA.

Keywords: POU3F3, miR-29a-3p, osteoarthritis, FOXO3, autophagy, cartilage extracellular matrix.

Graphical Abstract

[1]
Zeng C, Lane NE, Li X, et al. Association between bariatric surgery with long-term analgesic prescription and all-cause mortality among patients with osteoarthritis: A general population-based cohort study. Osteoarthritis Cartilage 2021; 29(10): 1412-7.
[http://dx.doi.org/10.1016/j.joca.2021.05.063] [PMID: 34293442]
[2]
Boyde A. The bone cartilage interface and osteoarthritis. Calcif Tissue Int 2021; 109(3): 303-28.
[http://dx.doi.org/10.1007/s00223-021-00866-9] [PMID: 34086084]
[3]
Mustonen AM, Nieminen P. Extracellular vesicles and their potential significance in the pathogenesis and treatment of osteoarthritis. Pharmaceuticals (Basel) 2021; 14(4): 315.
[http://dx.doi.org/10.3390/ph14040315] [PMID: 33915903]
[4]
Scanu A, Tognolo L, Maccarone MC, Masiero S. Immunological events, emerging pharmaceutical treatments and therapeutic potential of balneotherapy on osteoarthritis. Front Pharmacol 2021; 12: 681871.
[http://dx.doi.org/10.3389/fphar.2021.681871] [PMID: 34276372]
[5]
Hu Y, Chen X, Wang S, Jing Y, Su J. Subchondral bone microenvironment in osteoarthritis and pain. Bone Res 2021; 9(1): 20.
[http://dx.doi.org/10.1038/s41413-021-00147-z] [PMID: 33731688]
[6]
Peng Z, Sun H, Bunpetch V, et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials 2021; 268: 120555.
[http://dx.doi.org/10.1016/j.biomaterials.2020.120555] [PMID: 33285440]
[7]
Miao C, Zhou W, Wang X, Fang J. The research progress of exosomes in osteoarthritis, with particular emphasis on the mediating roles of miRNAs and lncRNAs. Front Pharmacol 2021; 12: 685623.
[http://dx.doi.org/10.3389/fphar.2021.685623] [PMID: 34093208]
[8]
Li X, Zhang L, Shi X, et al. MicroRNA-10a-3p improves cartilage degeneration by regulating CH25H-CYP7B1-RORα mediated cholesterol metabolism in knee osteoarthritis rats. Front Pharmacol 2021; 12: 690181.
[http://dx.doi.org/10.3389/fphar.2021.690181] [PMID: 34149433]
[9]
Wang XW, Liu CX, Chen LL, Zhang QC. RNA structure probing uncovers RNA structure-dependent biological functions. Nat Chem Biol 2021; 17(7): 755-66.
[http://dx.doi.org/10.1038/s41589-021-00805-7] [PMID: 34172967]
[10]
Grimson A. Linking microRNAs to their targets. Nat Chem Biol 2015; 11(2): 100-1.
[http://dx.doi.org/10.1038/nchembio.1741] [PMID: 25602729]
[11]
Yue X, Schwartz JC, Chu Y, et al. Transcriptional regulation by small RNAs at sequences downstream from 3′ gene termini. Nat Chem Biol 2010; 6(8): 621-9.
[http://dx.doi.org/10.1038/nchembio.400] [PMID: 20581822]
[12]
Nie T, Zhang C, Zhang G, et al. LncRNA CALML3-AS1 regulates chondrocyte apoptosis by acting as a sponge for miR-146a. Autoimmunity 2021; 54(6): 336-42.
[http://dx.doi.org/10.1080/08916934.2021.1943663] [PMID: 34282692]
[13]
He J, Wang L, Ding Y, Liu H, Zou G. lncRNA FER1L4 is dysregulated in osteoarthritis and regulates IL-6 expression in human chondrocyte cells. Sci Rep 2021; 11(1): 13032.
[http://dx.doi.org/10.1038/s41598-021-92474-8] [PMID: 34158566]
[14]
Xiao Y, Liu L, Zheng Y, Liu W, Xu Y. Kaempferol attenuates the effects of XIST/miR-130a/STAT3 on inflammation and extracellular matrix degradation in osteoarthritis. Future Med Chem 2021; 13(17): 1451-64.
[http://dx.doi.org/10.4155/fmc-2021-0127] [PMID: 34120462]
[15]
Wang J, Sun Y, Liu J, et al. Roles of long non coding RNA in osteoarthritis (Review). Int J Mol Med 2021; 48(1): 133.
[http://dx.doi.org/10.3892/ijmm.2021.4966] [PMID: 34013375]
[16]
Li Y, Li Z, Li C, Zeng Y, Liu Y. Long noncoding RNA TM1P3 is involved in osteoarthritis by mediating chondrocyte extracellular matrix degradation. J Cell Biochem 2019; 120(8): 12702-12.
[http://dx.doi.org/10.1002/jcb.28539] [PMID: 30887601]
[17]
Yu C, Shi D, Li Z, Wan G, Shi X. Retracted: Long noncoding RNA CHRF exacerbates IL‐6‐induced inflammatory damages by downregulating microRNA‐146a in ATDC5 cells. J Cell Physiol 2019; 234(12): 21851-9.
[http://dx.doi.org/10.1002/jcp.28749] [PMID: 31026064]
[18]
Li Y, Li S, Liu Y, Luo Y. Long noncoding RNA CIR promotes chondrocyte extracellular matrix degradation in osteoarthritis by acting as a sponge for Mir-27b. Cell Physiol Biochem 2017; 43(2): 602-10.
[http://dx.doi.org/10.1159/000480532]
[19]
Wang CL, Zuo B, Li D, et al. The long noncoding RNA H19 attenuates force-driven cartilage degeneration via miR-483–5p/Dusp5. Biochem Biophys Res Commun 2020; 529(2): 210-7.
[http://dx.doi.org/10.1016/j.bbrc.2020.05.180] [PMID: 32703413]
[20]
Belus MT, Rogers MA, Elzubeir A, et al. Kir2.1 is important for efficient BMP signaling in mammalian face development. Dev Biol 2018; 444(Suppl. 1): S297-307.
[http://dx.doi.org/10.1016/j.ydbio.2018.02.012] [PMID: 29571612]
[21]
Wu K, Wang Q, Liu YL, et al. LncRNA POU3F3 contributes to dacarbazine resistance of human melanoma through the MiR-650/MGMT axis. Front Oncol 2021; 11: 643613.
[http://dx.doi.org/10.3389/fonc.2021.643613] [PMID: 33816296]
[22]
Yan S, Du L, Jiang X, et al. Evaluation of serum exosomal lncRNAs as diagnostic and prognostic biomarkers for esophageal squamous cell carcinoma. Cancer Manag Res 2020; 12: 9753-63.
[http://dx.doi.org/10.2147/CMAR.S250971] [PMID: 33116835]
[23]
Zeng Q, Dai Y, Duan C, Zeng R, Zeng Q, Wei C. Long noncoding RNA POU3F3 enhances cancer cell proliferation, migration and invasion in non-small cell lung cancer (adenocarcinoma) by downregulating microRNA-30d-5p. BMC Pulm Med 2020; 20(1): 185.
[http://dx.doi.org/10.1186/s12890-020-01218-3] [PMID: 32615948]
[24]
Ling H, Zeng Q, Ge Q, et al. Osteoking decelerates cartilage degeneration in DMM-induced osteoarthritic mice model through TGF-β/smad-dependent Manner. Front Pharmacol 2021; 12: 678810.
[http://dx.doi.org/10.3389/fphar.2021.678810] [PMID: 34211396]
[25]
Luo Z, Hu Z, Bian Y, et al. Scutellarin attenuates the IL-1β-induced inflammation in mouse chondrocytes and prevents osteoarthritic progression. Front Pharmacol 2020; 11: 107.
[http://dx.doi.org/10.3389/fphar.2020.00107] [PMID: 32161544]
[26]
Zhang F, Wang K, Gao F, Xuan Y, Liu X, Zhang Z. Resveratrol pretreatment improved heart recovery ability of hyperglycemic bone marrow stem cells transplantation in diabetic myocardial infarction by down-regulating MicroRNA-34a. Front Pharmacol 2021; 12: 632375.
[http://dx.doi.org/10.3389/fphar.2021.632375] [PMID: 34177568]
[27]
Ruan G, Xu J, Wang K, et al. Associations between knee structural measures, circulating inflammatory factors and MMP13 in patients with knee osteoarthritis. Osteoarthritis Cartilage 2018; 26(8): 1063-9.
[http://dx.doi.org/10.1016/j.joca.2018.05.003] [PMID: 29753949]
[28]
Dyer J, Davison G, Marcora SM, Mauger AR. Effect of a Mediterranean type diet on inflammatory and cartilage degradation biomarkers in patients with osteoarthritis. J Nutr Health Aging 2017; 21(5): 562-6.
[http://dx.doi.org/10.1007/s12603-016-0806-y] [PMID: 28448087]
[29]
Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage 2015; 23(11): 1825-34.
[http://dx.doi.org/10.1016/j.joca.2015.08.015] [PMID: 26521728]
[30]
Yi H, Zhang W, Cui SY, Fan JB, Zhu XH, Liu W. Identification and validation of key long non-coding RNAs in resveratrol protect against IL-1β-treated chondrocytes via integrated bioinformatic analysis. J Orthop Surg Res 2021; 16(1): 421.
[http://dx.doi.org/10.1186/s13018-021-02574-4] [PMID: 34215299]
[31]
Sun H, Peng G, Ning X, Wang J, Yang H, Deng J. Emerging roles of long noncoding RNA in chondrogenesis, osteogenesis, and osteoarthritis. Am J Transl Res 2019; 11(1): 16-30.
[PMID: 30787967]
[32]
Wang H, Zhu H, Yang X. Dioscin exhibits anti-inflammatory effects in IL-1β-stimulated human osteoarthritis chondrocytes by activating LXRα. Immunopharmacol Immunotoxicol 2020; 42(4): 340-5.
[http://dx.doi.org/10.1080/08923973.2020.1775248] [PMID: 32515238]
[33]
Jia T, Qiao J, Guan D, Chen T. Anti-inflammatory effects of licochalcone A on IL-1β-stimulated human osteoarthritis chondrocytes. Inflammation 2017; 40(6): 1894-902.
[http://dx.doi.org/10.1007/s10753-017-0630-5] [PMID: 28756519]
[34]
Le LTT, Swingler TE, Crowe N, et al. The microRNA-29 family in cartilage homeostasis and osteoarthritis. J Mol Med (Berl) 2016; 94(5): 583-96.
[http://dx.doi.org/10.1007/s00109-015-1374-z] [PMID: 26687115]
[35]
Hu H, Zhang XW, Li L, et al. Inhibition of autophagy by YC-1 promotes gefitinib induced apoptosis by targeting FOXO1 in gefitinib-resistant NSCLC cells. Eur J Pharmacol 2021; 908: 174346.
[http://dx.doi.org/10.1016/j.ejphar.2021.174346] [PMID: 34270985]
[36]
Körholz K, Ridinger J, Krunic D, et al. Broad-spectrum HDAC inhibitors promote autophagy through FOXO transcription factors in neuroblastoma. Cells 2021; 10(5): 1001.
[http://dx.doi.org/10.3390/cells10051001] [PMID: 33923163]
[37]
Matsuzaki T, Alvarez-Garcia O, Mokuda S, et al. FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med 2018; 10(428): eaan0746.
[http://dx.doi.org/10.1126/scitranslmed.aan0746] [PMID: 29444976]
[38]
Akasaki Y, Alvarez-Garcia O, Saito M, Caramés B, Iwamoto Y, Lotz MK. FoxO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatol 2014; 66(12): 3349-58.
[http://dx.doi.org/10.1002/art.38868] [PMID: 25186470]
[39]
Mei R, Lou P, You G, Jiang T, Yu X, Guo L. 17β-Estradiol induces mitophagy upregulation to protect chondrocytes via the SIRT1-mediated AMPK/mTOR signaling pathway. Front Endocrinol (Lausanne) 2021; 11: 615250.
[http://dx.doi.org/10.3389/fendo.2020.615250] [PMID: 33613450]
[40]
Li Y, Wu Y, Jiang K, et al. Mangiferin prevents TBHP-induced apoptosis and ECM degradation in mouse osteoarthritic chondrocytes via restoring autophagy and ameliorates murine osteoarthritis. Oxid Med Cell Longev 2019; 2019: 8783197.
[http://dx.doi.org/10.1155/2019/8783197]