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m6A-mediated upregulation of AC008 promotes osteoarthritis progression through the miR-328-3p‒AQP1/ANKH axis

Chen Li|Zhang Ming|Yang Jiashu|Yang Dawei|Ma Yunfei|Tang Yuting|Xing Mengying|Li Lingyun|Jin Yucui|Ma Changyan
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2021.12|Experimental and Molecular Medicine|제53권 |pp. 1-12|DOI 10.1038/s12276-021-00696-7

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초록

Long noncoding RNAs (lncRNAs) have emerged as important regulators of osteoarthritis (OA), but the biological roles and clinical significance of most lncRNAs in OA are not fully understood. Microarray analysis was performed to identify differentially expressed lncRNAs, mRNAs, and miRNAs between normal and osteoarthritic cartilage. We found that AC008440.5 (abbreviated AC008), as well as AQP1 and ANKH, were highly expressed in osteoarthritic cartilage, whereas miR-328-3p was expressed at a low level in osteoarthritic cartilage. Functional assays showed that ectopic expression of AC008, AQP1, and ANKH significantly decreased chondrocyte viability and promoted chondrocyte apoptosis and extracellular matrix (ECM) degradation, whereas knockdown of AC008, AQP1, and ANKH resulted in the opposite effects. Moreover, miR-328-3p overexpression increased chondrocyte viability and attenuated chondrocyte apoptosis and ECM degradation, whereas inhibition of miR-328-3p resulted in the opposite effects. Bioinformatics analysis, RNA immunoprecipitation (RIP), and luciferase assays revealed that AC008 functioned as a competing endogenous RNA (ceRNA) to regulate miR-328-3p, which specifically targeted the AQP1 and ANKH genes. In addition, miR-328-3p significantly ameliorated MIA-induced OA, whereas AC008 accelerated OA progression in vivo. Furthermore, fat mass and obesity-associated (FTO)-mediated N6-methyladenosine demethylation downregulated AC008 transcription, while lower FTO expression led to upregulation of AC008 transcription in OA. In conclusion, our data reveal that AC008 plays a critical role in OA pathogenesis via the miR-328-3p‒AQP1/ANKH pathway, suggesting that AC008 may be a potential therapeutic target for OA.

Abstract

Long noncoding RNAs (lncRNAs) have emerged as important regulators of osteoarthritis (OA), but the biological roles and clinical significance of most lncRNAs in OA are not fully understood. Microarray analysis was performed to identify differentially expressed lncRNAs, mRNAs, and miRNAs between normal and osteoarthritic cartilage. We found that AC008440.5 (abbreviated AC008), as well as AQP1 and ANKH, were highly expressed in osteoarthritic cartilage, whereas miR-328-3p was expressed at a low level in osteoarthritic cartilage. Functional assays showed that ectopic expression of AC008, AQP1, and ANKH significantly decreased chondrocyte viability and promoted chondrocyte apoptosis and extracellular matrix (ECM) degradation, whereas knockdown of AC008, AQP1, and ANKH resulted in the opposite effects. Moreover, miR-328-3p overexpression increased chondrocyte viability and attenuated chondrocyte apoptosis and ECM degradation, whereas inhibition of miR-328-3p resulted in the opposite effects. Bioinformatics analysis, RNA immunoprecipitation (RIP), and luciferase assays revealed that AC008 functioned as a competing endogenous RNA (ceRNA) to regulate miR-328-3p, which specifically targeted the AQP1 and ANKH genes. In addition, miR-328-3p significantly ameliorated MIA-induced OA, whereas AC008 accelerated OA progression in vivo. Furthermore, fat mass and obesity-associated (FTO)-mediated N6-methyladenosine demethylation downregulated AC008 transcription, while lower FTO expression led to upregulation of AC008 transcription in OA. In conclusion, our data reveal that AC008 plays a critical role in OA pathogenesis via the miR-328-3p‒AQP1/ANKH pathway, suggesting that AC008 may be a potential therapeutic target for OA.

참고문헌 (52)

  1. Loeser, R. F., "Osteoarthritis : a disease of the joint as an organ", Arthritis Rheum, 64, pp.1697~1707 (2012)
  2. Glyn-Jones, S., "Osteoarthritis", Lancet, 386, pp.376~387 (2015)
  3. Wang, X., "Metabolic triggered inflammation in osteoarthritis", Osteoarthr. Cartil, 23, pp.22~30 (2015)
  4. Hwang, H. S., "Chondrocyte apoptosis in the pathogenesis of osteoarthritis", Int. J. Mol. Sci, 16, pp.26035~26054 (2015)
  5. Safiri, S., "Global, regional and national burden of osteoarthritis 1990-2017 : a systematic analysis of the Global Burden of Disease Study 2017", Ann. Rheum. Dis, 79, pp.819~828 (2020)
  6. Hunter, D. J., "Osteoarthritis", Lancet, 393, pp.1745~1759 (2019)
  7. Jin-Wu Nam, "Incredible RNA: Dual Functions of Coding and Noncoding", Molecules and Cells, 39(5), pp.367~374 (2016), 한국분자세포생물학회
  8. Eidem, T. M., "Noncoding RNAs : regulators of the mammalian transcription machinery", J. Mol. Biol, 428, pp.2652~2659 (2016)
  9. Bartel, D. P., "MicroRNAs : genomics, biogenesis, mechanism, and function", Cell, 116, pp.281~297 (2004)
  10. Huang, J., "The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression", Nat. Commun, 10, pp.2876~ (2019)
  11. Ji, M. L., "Precise targeting of miR-141", 200c cluster in chondrocytes attenuates osteoarthritis development, 2021, pp.80, 356~366
  12. Tu, J., "The emerging role of lncRNAs in chondrocytes from osteoarthritis patients", Biomed. Pharmacother, 131, pp.110642~ (2020)
  13. He, C. P., "The function of lncRNAs in the pathogenesis of osteoarthritis", Bone Jt. Res, 10, pp.122~133 (2021)
  14. Hu, J., "Long non-coding RNA HOTAIR promotes osteoarthritis progression via miR-17-5p", FUT2, Cell Death Dis, pp.2018, 9[DOI]
  15. Liu, Y., "Long non-coding RNA XIST contributes to osteoarthritis progression via miR-149-5p", DNMT3A axis, 2020, pp.128, 110349~
  16. Shi, C., "lncRNA-CRNDE regulates BMSC chondrogenic differentiation and promotes cartilage repair in osteoarthritis through SIRT1", SOX9, 2021, pp.476, 1881~1890
  17. Bao, Q., "alphaB-crystallin(CRYAB)regulates the proliferation, apoptosis, synthesis and degradation of extracellular matrix of chondrocytes in osteoarthritis", Exp. Cell Res, 382, pp.111459~ (2019)
  18. Mu, Y. R., "Overexpression of aquaporin 1 in synovium aggravates rat collagen-induced arthritis through regulating betacatenin signaling : an in vivo and in vitro study", J. Inflamm. Res, 13, pp.701~712 (2020)
  19. Williams, C. J., "The role of ANKH in pathologic mineralization of cartilage", Curr. Opin. Rheumatol, 28, pp.145~151 (2016)
  20. Tan, G. S., "Expanded RNA-binding activities of mammalian Argonaute 2", Nucleic Acids Res, 37, pp.7533~7545 (2009)
  21. Gurley, K. A., "Biochemical and genetic analysis of ANK in arthritis and bone disease", Am. J. Hum. Genet, 79, pp.1017~1029 (2006)
  22. Musumeci, G., "Aquaporin 1(AQP1)expression in experimentally induced osteoarthritic knee menisci : an in vivo and in vitro study", Tissue Cell, 45, pp.145~152 (2013)
  23. Zhao, B. S., "Post-transcriptional gene regulation by mRNA modifications", Nat. Rev. Mol. Cell Biol., 18, pp.31~42 (2017)
  24. Roundtree, I. A., "Dynamic RNA modifications in gene expression regulation", Cell, 169, pp.1187~1200 (2017)
  25. Zhou, Y., "SRAMP : prediction of mammalian N6-methyladenosine(m6A)sites based on sequence-derived features", Nucleic Acids Res, 44, pp.e91~ (2016)
  26. Panoutsopoulou, K., "The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index : a Mendelian randomisation study", Ann. Rheum. Dis, 73, pp.2082~2086 (2014)
  27. Fu, M., "Expression profile of long noncoding RNAs in cartilage from knee osteoarthritis patients", Osteoarthr. Cartil, 23, pp.423~432 (2015)
  28. Zhao, Y., "Synovial fluid-derived exosomal lncRNA PCGEM1 as biomarker for the different stages of osteoarthritis", Int. Orthop, 42, pp.2865~2872 (2018)
  29. Lei Su, "LncRNA MEG3 promotes recovery of knee osteoarthritis in rats through regulating VEGF expression", Panminerva Medica (2020), Edizioni Minerva Medica[DOI]
  30. Tan, F., "The fibroblast-like synoviocyte derived exosomal long non-coding RNA H19 alleviates osteoarthritis progression through the miR-106b5p", TIMP2 axis, 2020, pp.43, 1498~1509
  31. Katayama, S., "Antisense transcription in the mammalian transcriptome", Science, 309, pp.1564~1566 (2005)
  32. Rosok, O., "Systematic identification of sense-antisense transcripts in mammalian cells", Nat. Biotechnol, 22, pp.104~108 (2004)
  33. Tay, Y., "The multilayered complexity of ceRNA crosstalk and competition", Nature, 505, pp.344~352 (2014)
  34. Batista, P. J., "Long noncoding RNAs : cellular address codes in development and disease", Cell, 152, pp.1298~1307 (2013)
  35. Srivastava, A. K., "Inhibition of miR-328-3p impairs cancer stem cell function and prevents metastasis in ovarian cancer", Cancer Res, 79, pp.2314~2326 (2019)
  36. Shi, J., "miR-328-3p mediates the anti-tumor effect in osteosarcoma via directly targeting MMP-16", Cancer Cell Int, 19, pp.104~ (2019)
  37. Yu, Y., "lncRNA UCA1 functions as a ceRNA to promote prostate cancer progression via sponging miR143", Mol. Ther. Nucleic Acids, 19, pp.751~758 (2020)
  38. Chen, X., "lncRNA UCA1 promotes gefitinib resistance as a ceRNA to target FOSL2 by sponging miR-143 in non-small cell lung cancer", Mol. Ther. Nucleic Acids, 19, pp.643~653 (2020)
  39. Mobasheri, A., "Expression of aquaporin 1(AQP1)in human synovitis", Ann. Anat, 192, pp.116~121 (2010)
  40. Gao, H., "Aquaporin 1 contributes to chondrocyte apoptosis in a rat model of osteoarthritis", Int. J. Mol. Med, 38, pp.1752~1758 (2016)
  41. Haneda, M., "Depletion of aquaporin 1 decreased ADAMTS4 expression in human chondrocytes", Mol. Med. Rep, 17, pp.4874~4882 (2018)
  42. Wang, X., "N6-methyladenosine-dependent regulation of messenger RNA stability", Nature, 505, pp.117~120 (2014)
  43. Yang, Y., "Dynamic transcriptomic m(6)A decoration : writers, erasers, readers and functions in RNA metabolism", Cell Res, 28, pp.616~624 (2018)
  44. Panneerdoss, S., "Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression", Sci. Adv., 4, pp.eaar8263~ (2018)
  45. Weng, H., "METTL14 inhibits hematopoietic stem", progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification, 2018, pp.22, 191~205
  46. Deng, X., "RNA N(6)-methyladenosine modification in cancers : current status and perspectives", Cell Res, 28, pp.507~517 (2018)
  47. Wu, Y., "Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis", Nat. Commun, 9, pp.4772~ (2018)
  48. Liu, Q., "METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte", Biochem. Biophys. Res. Commun, 516, pp.22~27 (2019)
  49. Mo, X. B., "Genome-wide identification of N(6)-methyladenosine(m(6)A)SNPs associated with rheumatoid arthritis", Front. Genet, 9, pp.299~ (2018)
  50. Dina, C., "Variation in FTO contributes to childhood obesity and severe adult obesity", Nat. Genet, 39, pp.724~726 (2007)
  51. Scuteri, A., "Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits", PLoS Genet, 3, pp.e115~ (2007)
  52. Jia, G., "N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO", Nat. Chem. Biol, 7, pp.885~887 (2011)

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