LncRNA‑p21 promotes chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR‑451

Tang,Luping; Ding,Jianbo; Zhou,Guangju; Liu,Zhihai

doi:10.3892/mmr.2018.9506

LncRNA‑p21 promotes chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR‑451

Authors:
- Luping Tang
- Jianbo Ding
- Guangju Zhou
- Zhihai Liu
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Affiliations: Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
Published online on: September 24, 2018 https://doi.org/10.3892/mmr.2018.9506
Pages: 5295-5301

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Abstract

Osteoarthritis (OA) is the most common type of arthritis, and remains to be social and medical challenge. Thus, identifying novel molecular targets is important for the prevention and treatment of OA. Long noncoding RNAs (lncRNAs) have been reported to modulate various biological and pathological processes. The aim of the present study was to investigate the role of lncRNA‑p21 in OA and its underlying mechanism, in order to better understand the development of OA and its treatment. Chondrocytes were isolated from cartilage samples obtained from OA and normal patients. Chondrocytes were transfected with microRNA (miRNA/miR)‑451 mimics, miR‑451 inhibitor, pcDNA3.1(+)‑p21 or small interfering RNA‑p21. Flow cytometry was performed to analyze cell apoptosis and reverse transcription‑quantitative polymerase chain reaction was conducted to detect the expression of mRNAs and miRNAs. Cell Counting Kit‑8 assay was performed to detect cell viability. The results revealed that the level of lncRNA‑p21 was significantly upregulated in OA cartilage when compared with the normal cartilage. Silencing of lncRNA‑p21 increased cell viability and inhibited the apoptosis rate of chondrocytes in OA, while lncRNA‑p21 overexpression decreased cell viability and increased the apoptosis rate of chondrocytes in OA. Overexpression of lncRNA‑p21 suppressed the expression of miR‑451 while the silencing of lncRNA‑p21 reversed this effect. MiR‑451 inhibitor effectively inhibited the upregulatory effect of si‑p21 on miR‑451. The increased cell viability and decreased apoptosis rate induced by lncRNA‑p21 silencing was abolished by the miR‑451 inhibitor. MiR‑451 mimic effectively increased the downregulatory effect of pcDNA3.1‑lncRNA‑p21 on miR‑451. The decreased cell viability and increased apoptosis rate induced by the overexpression of lncRNA‑p21 was abolished by the miR‑451 mimic. Investigation into the underlying mechanism revealed that lncRNA‑p21 interacted with miRNA‑451. In addition, lncRNA‑p21 negatively regulated the expression of miR‑451. Furthermore, lncRNA‑p21 promoted the apoptosis of chondrocytes in OA by acting as a sponge for miR‑451. Thus, lncRNA‑p21 was proposed as a promising target for the treatment of OA.

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1	Corciulo C, Lendhey M, Wilder T, Schoen H, Cornelissen AS, Chang G, Kennedy OD and Cronstein BN: Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun. 8:150192017. View Article : Google Scholar : PubMed/NCBI
2	Iezaki T, Ozaki K, Fukasawa K, Inoue M, Kitajima S, Muneta T, Takeda S, Fujita H, Onishi Y, Horie T, et al: ATF3 deficiency in chondrocytes alleviates osteoarthritis development. J Pathol. 239:426–437. 2016. View Article : Google Scholar : PubMed/NCBI
3	Rufino AT, Rosa SC, Judas F, Mobasheri A, Lopes MC and Mendes AF: Expression and function of K(ATP) channels in normal and osteoarthritic human chondrocytes: Possible role in glucose sensing. J Cell Biochem. 114:1879–1889. 2013. View Article : Google Scholar : PubMed/NCBI
4	Delgado-Enciso I, Paz-Garcia J, Rodriguez-Hernandez A, Madrigal-Perez VM, Cabrera-Licona A, Garcia-Rivera A, Soriano-Hernandez AD, Cortes-Bazan JL, Galvan-Salazar HR, Valtierra-Alvarez J, et al: A promising novel formulation for articular cartilage regeneration: Preclinical evaluation of a treatment that produces SOX9 overexpression in human synovial fluid cells. Mol Med Rep. 17:3503–3510. 2018.PubMed/NCBI
5	Cui GH, Wang YY, Li CJ, Shi CH and Wang WS: Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis. Exp Ther Med. 12:3390–3400. 2016. View Article : Google Scholar : PubMed/NCBI
6	Bijlsma JW, Berenbaum F and Lafeber FP: Osteoarthritis: An update with relevance for clinical practice. Lancet. 377:2115–2126. 2011. View Article : Google Scholar : PubMed/NCBI
7	Goldring MB: Update on the biology of the chondrocyte and new approaches to treating cartilage diseases. Best Pract Res Clin Rheumatol. 20:1003–1025. 2006. View Article : Google Scholar : PubMed/NCBI
8	Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA and Duong LT: Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone. 38:234–243. 2006. View Article : Google Scholar : PubMed/NCBI
9	Allen KD, Choong PF, Davis AM, Dowsey MM, Dziedzic KS, Emery C, Hunter DJ, Losina E, Page AE, Roos EM, et al: Osteoarthritis: Models for appropriate care across the disease continuum. Best Pract Res Clin Rheumatol. 30:503–535. 2016. View Article : Google Scholar : PubMed/NCBI
10	Goldring MB: The role of the chondrocyte in osteoarthritis. Arthritis Rheum. 43:1916–1926. 2000. View Article : Google Scholar : PubMed/NCBI
11	Hwang HS and Kim HA: Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci. 16:26035–26054. 2015. View Article : Google Scholar : PubMed/NCBI
12	Frank S, Aguirre A, Hescheler J and Kurian L: A lncRNA perspective into (Re)building the heart. Front Cell Dev Biol. 4:1282016. View Article : Google Scholar : PubMed/NCBI
13	Su Y, Wu H, Pavlosky A, Zou LL, Deng X, Zhang ZX and Jevnikar AM: Regulatory non-coding RNA: new instruments in the orchestration of cell death. Cell Death Dis. 7:e23332016. View Article : Google Scholar : PubMed/NCBI
14	Song J, Ahn C, Chun CH and Jin EJ: A long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis. J Orthop Res. 32:1628–1635. 2014. View Article : Google Scholar : PubMed/NCBI
15	Colombo T, Farina L, Macino G and Paci P: PVT1: A rising star among oncogenic long noncoding RNAs. Biomed Res Int. 2015:3042082015. View Article : Google Scholar : PubMed/NCBI
16	Liu Q, Zhang X, Dai L, Hu X, Zhu J, Li L, Zhou C and Ao Y: Long noncoding RNA related to cartilage injury promotes chondrocyte extracellular matrix degradation in osteoarthritis. Arthritis Rheumatol. 66:969–978. 2014. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Li S, Luo Y, Liu Y and Yu N: LncRNA PVT1 regulates chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR-488-3p. DNA Cell Biol. 36:571–580. 2017. View Article : Google Scholar : PubMed/NCBI
18	Dimitrova N, Zamudio JR, Jong RM, Soukup D, Resnick R, Sarma K, Ward AJ, Raj A, Lee JT, Sharp PA and Jacks T: LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol Cell. 54:777–790. 2014. View Article : Google Scholar : PubMed/NCBI
19	Yang F, Zhang H, Mei Y and Wu M: Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect. Mol Cell. 53:88–100. 2014. View Article : Google Scholar : PubMed/NCBI
20	Han W and Liu J: LncRNA-p21 inhibited the proliferation of osteosarcoma cells via the miR-130b/PTEN/AKT signaling pathway. Biomed Pharmacother. 97:911–918. 2018. View Article : Google Scholar : PubMed/NCBI
21	Musumeci G, Loreto C, Carnazza ML and Martinez G: Characterization of apoptosis in articular cartilage derived from the knee joints of patients with osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 19:307–313. 2011. View Article : Google Scholar : PubMed/NCBI
22	Musumeci G, Loreto C, Leonardi R, Castorina S, Giunta S, Carnazza ML, Trovato FM, Pichler K and Weinberg AM: The effects of physical activity on apoptosis and lubricin expression in articular cartilage in rats with glucocorticoid-induced osteoporosis. J Bone Miner Metab. 31:274–284. 2013. View Article : Google Scholar : PubMed/NCBI
23	Musumeci G, Castrogiovanni P, Trovato FM, Weinberg AM, Al-Wasiyah MK, Alqahtani MH and Mobasheri A: Biomarkers of chondrocyte apoptosis and autophagy in osteoarthritis. Int J Mol Sci. 16:20560–20575. 2015. View Article : Google Scholar : PubMed/NCBI
24	Musumeci G, Castrogiovanni P, Loreto C, Castorina S, Pichler K and Weinberg AM: Post-traumatic caspase-3 expression in the adjacent areas of growth plate injury site: A morphological study. Int J Mol Sci. 14:15767–15784. 2013. View Article : Google Scholar : PubMed/NCBI
25	Liu Y, Zhu H, Yan X, Gu H, Gu Z and Liu F: Endoplasmic reticulum stress participates in the progress of senescence and apoptosis of osteoarthritis chondrocytes. Biochem Biophys Res Commun. 491:368–373. 2017. View Article : Google Scholar : PubMed/NCBI
26	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
27	Zhu J, Zheng Y, Zhang H and Sun H: Targeting cancer cell metabolism: The combination of metformin and 2-Deoxyglucose regulates apoptosis in ovarian cancer cells via p38 MAPK/JNK signaling pathway. Am J Transl Res. 8:4812–4821. 2016.PubMed/NCBI
28	Zhu J, Zheng Y, Zhang H, Zhu J and Sun H: Low concentration of chloroquine enhanced efficacy of cisplatin in the treatment of human ovarian cancer dependent on autophagy. Am J Transl Res. 9:4046–4058. 2017.PubMed/NCBI
29	Perry RB and Ulitsky I: The functions of long noncoding RNAs in development and stem cells. Development. 143:3882–3894. 2016. View Article : Google Scholar : PubMed/NCBI
30	Tay Y, Karreth FA and Pandolfi PP: Aberrant ceRNA activity drives lung cancer. Cell Res. 24:259–260. 2014. View Article : Google Scholar : PubMed/NCBI
31	Kang Y, Song J, Kim D, Ahn C, Park S, Chun CH and Jin EJ: PCGEM1 stimulates proliferation of osteoarthritic synoviocytes by acting as a sponge for miR-770. J Orthop Res. 34:412–418. 2016. View Article : Google Scholar : PubMed/NCBI
32	Zhang G, Wu Y, Xu D and Yan X: Long noncoding RNA UFC1 promotes proliferation of chondrocyte in osteoarthritis by acting as a sponge for miR-34a. DNA Cell Biol. 35:691–695. 2016. View Article : Google Scholar : PubMed/NCBI
33	Yang N, Fu Y, Zhang H, Sima H, Zhu N and Yang G: LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma. Oncotarget. 6:28151–28163. 2015.PubMed/NCBI
34	Wang X, Ruan Y, Wang X, Zhao W, Jiang Q, Jiang C, Zhao Y, Xu Y, Sun F, Zhu Y, et al: Long intragenic non-coding RNA lincRNA-p21 suppresses development of human prostate cancer. Cell Prolif. 50:e123182017. View Article : Google Scholar
35	Wang G, Li Z, Zhao Q, Zhu Y, Zhao C, Li X, Ma Z, Li X and Zhang Y: LincRNA-p21 enhances the sensitivity of radiotherapy for human colorectal cancer by targeting the Wnt/β-catenin signaling pathway. Oncol Rep. 31:1839–1845. 2014. View Article : Google Scholar : PubMed/NCBI
36	Yang W, Yu H, Shen Y, Liu Y, Yang Z and Sun T: MiR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/β-catenin pathway. Oncotarget. 7:41505–41526. 2016.PubMed/NCBI