Identification of microRNA‑363‑3p as an essential regulator of chondrocyte apoptosis in osteoarthritis by targeting NRF1 through the p53‑signaling pathway

Zhang,Miao; Wang,Zhiqiang; Li,Baojie; Sun,Fengyi; Chen,Anzhong; Gong,Mingzhi

doi:10.3892/mmr.2020.10940

Identification of microRNA‑363‑3p as an essential regulator of chondrocyte apoptosis in osteoarthritis by targeting NRF1 through the p53‑signaling pathway

Authors:
- Miao Zhang
- Zhiqiang Wang
- Baojie Li
- Fengyi Sun
- Anzhong Chen
- Mingzhi Gong
View Affiliations

Affiliations: Department of Trauma and Orthopedics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Traumatic Orthopedics, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China, Department of Gynaecology, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China, Department of Rehabilitation, The Second People's Hospital of Liaocheng, Linqing, Shandong 252600, P.R. China
Published online on: January 14, 2020 https://doi.org/10.3892/mmr.2020.10940
Pages: 1077-1088
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Osteoarthritis (OA) is a degenerative joint disease that affects the physical, and mental health of middle‑aged and elderly people. The aims of the present study were to determine the biological function and molecular mechanisms of miR‑363‑3p in chondrocyte apoptosis. Exploration of the molecular mechanisms of OA may be helpful in the understand of the causes, and facilitating the prevention and treatment of OA. In the present study, the expression of nuclear respiratory factor1 (NRF1) was downregulated in the articular cartilage of OA rats in vivo and lipopolysaccharide (LPS)‑treated chondrocytes in vitro. MicroRNAs (miRNA) are regulators of gene expression in the progression of OA. TargetScan software was used to predict that NRF1 was a potential target for miRNA (miR)‑363, and this was confirmed in subsequent experiments. The expression of miR‑363‑3p was negatively correlated with the expression of NRF1, and its expression was significantly upregulated in OA model rats and in LPS‑induced chondrocytes compared with the expression in the respective controls. In addition, the overexpression of miR‑363‑3p increased the levels of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α in vivo, and was demonstrated to promote chondrocyte injury and apoptosis by Safranin O staining and TUNEL. Moreover, the inhibition of miR‑363‑3p expression increased the expression of NRF1 and protected chondrocytes from apoptosis in vitro and in vivo, whereas the overexpression of miR‑363‑3p downregulated NRF1 expression and promoted LPS‑induced chondrocyte apoptosis through the p53 pathway in vitro. The results of this study suggested that miR‑363‑3p‑mediated inhibition of NRF1may be associated with chondrocyte apoptosis in OA.

View Figures

View References

1	Xie F, Kovic B, Jin X, He X, Wang M and Silvestre C: Economic and humanistic burden of osteoarthritis: A systematic review of large sample studies. Pharmacoeconomics. 34:1087–1100. 2016. View Article : Google Scholar : PubMed/NCBI
2	Gu YT, Chen J, Meng ZL, Ge WY, Bian YY, Cheng SW, Xing CK, Yao JL, Fu J and Peng L: Research progress on osteoarthritis treatment mechanisms. Biomed Pharmacother. 93:1246–1252. 2017. View Article : Google Scholar : PubMed/NCBI
3	Barnett R: Osteoarthritis. Lancet. 391:19852018. View Article : Google Scholar : PubMed/NCBI
4	Ribitsch I, Mayer RL, Egerbacher M, Gabner S, Kańduła MM, Rosser J, Haltmayer E, Auer U, Gültekin S, Huber J, et al: Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: Secretome proteomics unravels molecular mechanisms in an ovine model. Dis Model Mech. 11:dmm0330922018. View Article : Google Scholar : PubMed/NCBI
5	Kim JH, Jeon J, Shin M, Won Y, Lee M, Kwak JS, Lee G, Rhee J, Ryu JH, Chun CH and Chun JS: Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell. 156:730–743. 2014. View Article : Google Scholar : PubMed/NCBI
6	Ma F, Li G, Yu Y, Xu J and Wu X: MiR-33b-3p promotes chondrocyte proliferation and inhibits chondrocyte apoptosis and cartilage ECM degradation by targeting DNMT3A in osteoarthritis. Biochem Biophys Res Commun. 519:430–437. 2019. View Article : Google Scholar : PubMed/NCBI
7	Evans MJ and Scarpulla RC: NRF-1: A trans-activator of nuclear-encoded respiratory genes in animal cells. Genes Dev. 4:1023–1034. 1990. View Article : Google Scholar : PubMed/NCBI
8	Scarpulla RC: Nuclear respiratory factors and the pathways of nuclear-mitochondrial interaction. Trends Cardiovasc Med. 6:39–45. 1996. View Article : Google Scholar : PubMed/NCBI
9	Zhang Y and Manning BD: mTORC1 signaling activates NRF1 to increase cellular proteasome levels. Cell Cycle. 14:2011–2017. 2015. View Article : Google Scholar : PubMed/NCBI
10	Zhang GM, Deng MT, Lei ZH, Wan YJ, Nie HT, Wang ZY, Fan YX, Wang F and Zhang YL: Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells. Reproduction. 154:111–122. 2017. View Article : Google Scholar : PubMed/NCBI
11	Niu N, Li Z, Zhu M, Sun H, Yang J, Xu S, Zhao W and Song R: Effects of nuclear respiratory factor1 on apoptosis and mitochondrial dysfunction induced by cobalt chloride in H9C2 cells. Mol Med Rep. 19:2153–2163. 2019.PubMed/NCBI
12	Zhang H, Wu J, Keller JM, Yeung K, Keller ET and Fu Z: Transcriptional regulation of RKIP expression by androgen in prostate cells. Cell Physiol Biochem. 30:1340–1350. 2012. View Article : Google Scholar : PubMed/NCBI
13	Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH and Cuppen E: Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 120:21–24. 2005. View Article : Google Scholar : PubMed/NCBI
14	Zhang S, Chen L, Jung EJ and Calin GA: Targeting microRNAs with small molecules: From dream to reality. Clin Pharmacol Ther. 87:754–758. 2010. View Article : Google Scholar : PubMed/NCBI
15	Bao J, Li D, Wang L, Wu J, Hu Y, Wang Z, Chen Y, Cao X, Jiang C, Yan W and Xu C: MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway. J Biol Chem. 287:21686–21698. 2012. View Article : Google Scholar : PubMed/NCBI
16	Zhao Z, Dai XS, Wang ZY, Bao ZQ and Guan JZ: MicroRNA-26a reduces synovial inflammation and cartilage injury in osteoarthritis of knee joints through impairing the NF-κB signaling pathway. Biosci Rep. 39:BSR201820252019. View Article : Google Scholar : PubMed/NCBI
17	Ma Y, Wu Y, Chen J, Huang K, Ji B, Chen Z, Wang Q, Ma J, Shen S and Zhang J: miR-10a-5p promotes chondrocyte apoptosis in osteoarthritis by targeting HOXA1. Mol Ther Nucleic Acids. 14:398–409. 2019. View Article : Google Scholar : PubMed/NCBI
18	Ding Y, Wang L, Zhao Q, Wu Z and Kong L: MicroRNA93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF-κB signaling pathway. Int J Mol Med. 43:779–790. 2019.PubMed/NCBI
19	Witkos TM, Koscianska E and Krzyzosiak WJ: Practical aspects of microRNA target prediction. Curr Mol Med. 11:93–109. 2011. View Article : Google Scholar : PubMed/NCBI
20	Meng X, Ji Y, Wan Z, Zhao B, Feng C, Zhao J, Li H and Song Y: Inhibition of miR-363 protects cardiomyocytes against hypoxia-induced apoptosis through regulation of Notch signaling. Biomed Pharmacother. 90:509–516. 2017. View Article : Google Scholar : PubMed/NCBI
21	Wenzhao L, Jiangdong N, Deye S, Muliang D, Junjie W, Xianzhe H, Mingming Y and Jun H: Dually regulatory roles of HMGB1 in inflammatory reaction of chondrocyte cells and mice. Cell Cycle. 18:2268–2280. 2019. View Article : Google Scholar : PubMed/NCBI
22	Ni Z, Kuang L, Chen H, Xie Y, Zhang B, Ouyang J, Wu J, Zhou S, Chen L, Su N, et al: The exosome-like vesicles from osteoarthritic chondrocyte enhanced mature IL-1β production of macrophages and aggravated synovitis in osteoarthritis. Cell Death Dis. 10:5222019. View Article : Google Scholar : PubMed/NCBI
23	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 : PubMed/NCBI
24	Mankin HJ: Biochemical and metabolic abnormalities in osteoarthritic human cartilage. Fed Proc. 32:1478–1480. 1973.PubMed/NCBI
25	Pope JE, McCrea K, Stevens A and Ouimet JM: The relationship between NSAID use and osteoarthritis (OA) severity in patients with hip and knee OA: Results of a case control study of NSAID use comparing those requiring hip and knee replacements to those in whom surgery was not recommended. Med Sci Monit. 14:CR604–CR610. 2008.PubMed/NCBI
26	Onuora S: Osteoarthritis: Cartilage matrix stiffness regulates chondrocyte metabolism and OA pathogenesis. Nat Rev Rheumatol. 11:5042015. View Article : Google Scholar
27	Yudoh K and Karasawa R: Statin prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis (OA). Aging (Albany NY). 2:990–998. 2010. View Article : Google Scholar : PubMed/NCBI
28	Héraud F, Héraud A and Harmand MF: Apoptosis in normal and osteoarthritic human articular cartilage. Ann Rheum Dis. 59:959–965. 2000. View Article : Google Scholar : PubMed/NCBI
29	Sant KE, Hansen JM, Williams LM, Tran NL, Goldstone JV, Stegeman JJ, Hahn ME and Timme-Laragy A: The role of NRF1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo. Redox Biol. 13:207–218. 2017. View Article : Google Scholar : PubMed/NCBI
30	Zhang J, Gu JY, Chen ZS, Xing KC and Sun B: Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: The role of NRF1 and antioxidant response. Int J Clin Exp Pathol. 8:2515–2524. 2015.PubMed/NCBI
31	Su Z, Yang Z, Xu Y, Chen Y and Yu Q: MicroRNAs in apoptosis, autophagy and necroptosis. Oncotarget. 6:8474–8490. 2015. View Article : Google Scholar : PubMed/NCBI
32	Teng YL, Ren F, Xu H and Song HJ: Overexpression of miRNA- 410-3p protects hypoxia-induced cardiomyocyte injury via targeting TRAF5. Eur Rev Med Pharmacol Sci. 23:9050–9057. 2019.PubMed/NCBI
33	Jiang L, Ge W and Geng J: miR-425 regulates cell proliferation, migration and apoptosis by targeting AMPH-1 in non-small-cell lung cancer. Pathol Res Pract. 215:1527052019. View Article : Google Scholar : PubMed/NCBI
34	Wu G, Tan J, Li J, Sun X, Du L and Tao S: miRNA-145-5p induces apoptosis after ischemia-reperfusion by targeting dual specificity phosphatase 6. J Cell Physiol. Mar 18–2019.doi: 10.1002/jcp.28291 (Epub ahead of print).
35	Feng WT, Yao R, Xu LJ, Zhong XM, Liu H, Sun Y and Zhou LL: Effect of miR-363 on the proliferation, invasion and apoptosis of laryngeal cancer by targeting Mcl-1. Eur Rev Med Pharmacol Sci. 22:4564–4572. 2018.PubMed/NCBI
36	Dong J, Geng J and Tan W: MiR-363-3p suppresses tumor growth and metastasis of colorectal cancer via targeting SphK2. Biomed Pharmacother. 105:922–931. 2018. View Article : Google Scholar : PubMed/NCBI
37	Lee KH and Kang TB: The molecular links between cell death and inflammasome. Cells. 8:E10572019. View Article : Google Scholar : PubMed/NCBI
38	Zhu Y, Saito K, Murakami Y, Asano M, Iwakura Y and Seishima M: Early increase in mRNA levels of pro-inflammatory cytokines and their interactions in the mouse hippocampus after transient global ischemia. Neurosci Lett. 393:122–126. 2006. View Article : Google Scholar : PubMed/NCBI
39	Liu T, Bao YH, Wang Y and Jiang JY: The role of necroptosis in neurosurgical diseases. Braz J Med Biol Res. 48:292–298. 2015. View Article : Google Scholar : PubMed/NCBI
40	Tsujimoto Y, Cossman J, Jaffe E and Croce CM: Involvement of the bcl-2 gene in human follicular lymphoma. Science. 228:1440–1443. 1985. View Article : Google Scholar : PubMed/NCBI
41	Liu C, Shi Z, Fan L, Zhang C, Wang K and Wang B: Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res. 1374:100–109. 2011. View Article : Google Scholar : PubMed/NCBI
42	Clark WM, Rinker LG, Lessov NS, Hazel K, Hill JK, Stenzel-Poore M and Eckenstein F: Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke. 31:1715–1720. 2000. View Article : Google Scholar : PubMed/NCBI
43	Glushakova OY, Glushakov AA, Wijesinghe DS, Valadka AB, Hayes RL and Glushakov AV: Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration. Brain Circ. 3:87–108. 2017.PubMed/NCBI
44	Fridman JS and Lowe SW: Control of apoptosis by p53. Oncogene. 22:9030–9040. 2003. View Article : Google Scholar : PubMed/NCBI
45	Lu Q, Rau TF, Harris V, Johnsonm M, Poulsen DJ and Black SM: Increased p38 mitogen-activated protein kinase signaling is involved in the oxidative stress associated with oxygen and glucose deprivation in neonatal hippocampal slice cultures. Eur J Neurosci. 34:1093–1101. 2011. View Article : Google Scholar : PubMed/NCBI