circPhc3 sponging microRNA‑93‑3p is involved in the regulation of chondrocyte function by mechanical instability in osteoarthritis

Wang,Zhiyuan; Rao,Zhitao; Wang,Xin; Jiang,Chao; Yang,Yi

doi:10.3892/ijmm.2021.5061

circPhc3 sponging microRNA‑93‑3p is involved in the regulation of chondrocyte function by mechanical instability in osteoarthritis

Authors:
- Zhiyuan Wang
- Zhitao Rao
- Xin Wang
- Chao Jiang
- Yi Yang
View Affiliations

Affiliations: Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China
Published online on: November 10, 2021 https://doi.org/10.3892/ijmm.2021.5061
Article Number: 6
Copyright: © Wang 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

Cartilage extracellular matrix (ECM) metabolism disorder caused by mechanical instability is a leading cause of osteoarthritis (OA), but the exact mechanisms have not been fully elucidated. Recent studies have suggested an important role of circular RNAs (circRNAs/circs) in OA. The present study aimed to investigate whether circRNAs might have a role in mechanical instability‑regulated chondrocyte matrix metabolism in OA. The expression levels of circPhc3 in human and mouse OA cartilage samples were measured using reverse transcription‑quantitative PCR and fluorescence in situ hybridization. The effects of circPhc3 on chondrocyte ECM metabolism were further investigated by overexpressing and knocking down circPhc3 in OA chondrocytes. The downstream target of circPhc3 was examined by performing a luciferase reporter assay. The results showed that the expression of circPhc3 was reduced in human and mouse OA cartilage. Moreover, circPhc3 was involved in mechanical loading‑regulated production of ECM and cartilage‑degrading enzymes. Further studies showed that circPhc3 regulated chondrocyte matrix metabolism primarily by binding to microRNA (miR)‑93‑3p, and mechanistic studies found that miR‑93‑3p targeting of FoxO1 was involved in chondrocyte matrix metabolism. Taken together, these results indicated that circPhc3 may serve an important role in the progression of OA and may be a good target for the treatment of OA.

View Figures

View References

1	Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, et al: Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 23:775–781. 2017. View Article : Google Scholar : PubMed/NCBI
2	Palazzo C, Nguyen C, Lefevre-Colau MM, Rannou F and Poiraudeau S: Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 59:134–138. 2016. View Article : Google Scholar : PubMed/NCBI
3	Sakata R, Iwakura T and Reddi AH: Regeneration of articular cartilage surface: Morphogens, cells, and extracellular matrix scaffolds. Tissue Eng Part B Rev. 21:461–473. 2015. View Article : Google Scholar : PubMed/NCBI
4	Murata D, Fujimoto R and Nakayama K: Osteochondral regeneration using adipose tissue-derived mesenchymal stem cells. Int J Mol Sci. 21:35892020. View Article : Google Scholar :
5	Vela-Anero A, Hermida-Gomez T, Gato-Calvo L, Vaamonde-García C, Díaz-Prado S, Meijide-Faílde R, Blanco FJ and Burguera EF: Long-term effects of hydrogen sulfide on the anabolic-catabolic balance of articular cartilage in vitro. Nitric Oxide. 70:42–50. 2017. View Article : Google Scholar : PubMed/NCBI
6	Anderson DE, Markway BD, Weekes KJ, McCarthy HE and Johnstone B: Physioxia promotes the articular chondrocyte-like phenotype in human chondroprogenitor-derived self-organized tissue. Tissue Eng Part A. 24:264–274. 2018. View Article : Google Scholar :
7	Guilak F: Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 25:815–823. 2011. View Article : Google Scholar
8	Onitsuka K, Murata K, Kokubun T, Fujiwara S, Nakajima A, Morishita Y and Kanemura N: Effects of controlling abnormal joint movement on expression of MMP13 and TIMP-1 in osteoarthritis. Cartilage. 11:98–107. 2020. View Article : Google Scholar :
9	Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB and Kjems J: The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 20:675–691. 2019. View Article : Google Scholar : PubMed/NCBI
10	Zhou ZB, Huang GX, Fu Q, Han B, Lu JJ, Chen AM and Zhu L: circRNA.33186 contributes to the pathogenesis of osteoarthritis by sponging miR-127-5p. Mol Ther. 27:531–541. 2019. View Article : Google Scholar : PubMed/NCBI
11	Shen S, Wu Y, Chen J, Xie Z, Huang K, Wang G, Yang Y, Ni W, Chen Z, Shi P, et al: CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene. Ann Rheum Dis. 78:826–836. 2019. View Article : Google Scholar : PubMed/NCBI
12	Shen P, Yang Y, Liu G, Chen W, Chen J, Wang Q, Gao H, Fan S, Shen S, Zhao X, et al: CircCDK14 protects against osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2. Theranostics. 10:9113–9131. 2020. View Article : Google Scholar : PubMed/NCBI
13	Yu CX and Sun S: An emerging role for circular RNAs in osteoarthritis. Yonsei Med J. 59:349–355. 2018. View Article : Google Scholar : PubMed/NCBI
14	Thomson DW and Dinger ME: Endogenous microRNA sponges: Evidence and controversy. Nat Rev Genet. 17:272–283. 2016. View Article : Google Scholar : PubMed/NCBI
15	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013. View Article : Google Scholar : PubMed/NCBI
16	Kellgren JH and Lawrence JS: Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 16:494–502. 1957. View Article : Google Scholar : PubMed/NCBI
17	Jeon OH, Wilson DR, Clement CC, Rathod S, Cherry C, Powell B, Lee Z, Khalil AM, Green JJ, Campisi J, et al: Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight. 4:e1250192019. View Article : Google Scholar
18	Yang F, Huang R, Ma H, Zhao X and Wang G: miRNA-411 regulates chondrocyte autophagy in osteoarthritis by targeting hypoxia-inducible factor 1 alpha (HIF-1α). Med Sci Monit. 26:e9211552020.
19	Weiss S, Hennig T, Bock R, Steck E and Richter W: Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. J Cell Physiol. 223:84–93. 2010.PubMed/NCBI
20	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
21	Blalock D, Miller A, Tilley M and Wang J: Joint instability and osteoarthritis. Clin Med Insights Arthritis Musculoskelet Disord. 8:15–23. 2015. View Article : Google Scholar : PubMed/NCBI
22	Guilak F, Fermor B, Keefe FJ, Kraus VB, Olson SA, Pisetsky DS, Setton LA and Weinberg JB: The role of biomechanics and inflammation in cartilage injury and repair. Clin Orthop Relat Res. 423:17–26. 2004. View Article : Google Scholar
23	Wang T, Hao Z, Liu C, Yuan L, Li L, Yin M, Li Q, Qi Z and Wang Z: LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF κB signaling pathway. Cell Death Dis. 11:5982020. View Article : Google Scholar
24	Chen C: Serum hsa_circ_101178 as a potential biomarker for early prediction of osteoarthritis. Clin Lab. View Article : Google Scholar
25	Shen S, Yang Y, Shen P, Ma J, Fang B, Wang Q, Wang K, Shi P, Fan S and Fang X: circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1. Ann Rheum Dis. 80:1209–1219. 2021. View Article : Google Scholar : PubMed/NCBI
26	Ehrlich GD: Circular RNAs as diagnostic biomarkers for osteoarthritis. Genet Test Mol Biomarkers. 23:701–702. 2019. View Article : Google Scholar : PubMed/NCBI
27	Liu Q, Zhang X, Hu X, Dai L, Fu X, Zhang J and Ao Y: Circular RNA related to the chondrocyte ECM regulates MMP13 Expression by functioning as a miR-136 'Sponge' in human cartilage degradation. Sci Rep. 6:225722016. View Article : Google Scholar : PubMed/NCBI
28	Li BF, Zhang Y, Xiao J, Wang F, Li M, Guo XZ, Xie HB, Xia H and Chen B: Hsa_circ_0045714 regulates chondrocyte proliferation, apoptosis and extracellular matrix synthesis by promoting the expression of miR-193b target gene IGF1R. Hum Cell. 30:311–318. 2017. View Article : Google Scholar : PubMed/NCBI
29	Liu Q, Zhang X, Hu X, Yuan L, Cheng J, Jiang Y and Ao Y: Emerging roles of circRNA related to the mechanical stress in human cartilage degradation of osteoarthritis. Mol Ther Nucleic Acids. 7:223–230. 2017. View Article : Google Scholar : PubMed/NCBI
30	Xiang Q, Kang L, Zhao K, Wang J, Hua W, Song Y, Feng X, Li G, Lu S, Wang K, et al: CircCOG8 downregulation contributes to the compression-induced intervertebral disk degeneration by targeting miR-182-5p and FOXO3. Front Cell Dev Biol. 8:5819412020. View Article : Google Scholar : PubMed/NCBI
31	Wang H, Feng C, Jin Y, Tan W and Wei F: Identification and characterization of circular RNAs involved in mechanical force-induced periodontal ligament stem cells. J Cell Physiol. 234:10166–10177. 2019. View Article : Google Scholar
32	Xiao L, Ding B, Xu S, Gao J, Yang B, Wang J and Xu H: circRNA_0058097 promotes tension-induced degeneration of endplate chondrocytes by regulating HDAC4 expression through sponge adsorption of miR-365a-5p. J Cell Biochem. 121:418–429. 2020. View Article : Google Scholar
33	Zhu X, Du J and Gu Z: Circ-PVT1/miR-106a-5p/HK2 axis regulates cell growth, metastasis and glycolytic metabolism of oral squamous cell carcinoma. Mol Cell Biochem. 474:147–158. 2020. View Article : Google Scholar : PubMed/NCBI
34	Tang B, Xuan L, Tang M, Wang H, Zhou J, Liu J, Wu S, Li M, Wang X and Zhang H: miR-93-3p alleviates lipopolysaccharide-induced inflammation and apoptosis in H9c2 cardiomyocytes by inhibiting toll-like receptor 4. Pathol Res Pract. 214:1686–1693. 2018. View Article : Google Scholar : PubMed/NCBI
35	Butler AE, Ramachandran V, Hayat S, Dargham SR, Cunningham TK, Benurwar M, Sathyapalan T, Najafi-Shoushtari SH and Atkin SL: Expression of microRNA in follicular fluid in women with and without PCOS. Sci Rep. 9:163062019. View Article : Google Scholar : PubMed/NCBI
36	Peng W, Zhu SX, Wang J, Chen LL, Weng JQ and Chen SL: Lnc-NTF3-5 promotes osteogenic differentiation of maxillary sinus membrane stem cells via sponging miR-93-3p. Clin Implant Dent Relat Res. 20:110–121. 2018. View Article : Google Scholar
37	Mäkitie RE, Hackl M, Weigl M, Frischer A, Kämpe A, Costantini A, Grillari J and Mäkitie O: Unique, gender-dependent serum microRNA profile in PLS3 gene-related osteoporosis. J Bone Miner Res. 35:1962–1973. 2020. View Article : Google Scholar : PubMed/NCBI
38	Wang C, Shen J, Ying J, Xiao D and O'Keefe RJ: FoxO1 is a crucial mediator of TGF-β/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis. Proc Natl Acad Sci USA. 117:30488–30497. 2020. View Article : Google Scholar
39	Lee KI, Choi S, Matsuzaki T, Alvarez-Garcia O, Olmer M, Grogan SP, D'Lima DD and Lotz MK: FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis. Proc Natl Acad Sci USA. 117:3135–3143. 2020. View Article : Google Scholar : PubMed/NCBI
40	Akasaki Y, Alvarez-Garcia O, Saito M, Carames B, Iwamoto Y and Lotz MK: FoxO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatol. 66:3349–3358. 2014. View Article : Google Scholar : PubMed/NCBI
41	Miao X, Xi Z, Zhang Y, Li Z, Huang L, Xin T, Shen R and Wang T: Circ-SMARCA5 suppresses colorectal cancer progression via downregulating miR-39-3p and upregulating ARID4B. Dig Liver Dis. 52:1494–1502. 2020. View Article : Google Scholar : PubMed/NCBI
42	Zhu Y, Wang Y, Zhao J, Shen J, Wang Z, Bai M, Fan Y, Yin R, Mao Y and Bai W: CircRNA-1967 participates in the differentiation of goat SHF-SCs into hair follicle lineage by sponging miR-93-3p to enhance LEF1 expression. Anim Biotechnol. 22:1–13. 2021. View Article : Google Scholar