Journal of Biosciences

, 44:128 | Cite as

Long non-coding RNA H19 modulates proliferation and apoptosis in osteoarthritis via regulating miR-106a-5p

  • Xiaojun Zhang
  • Xiaomei LiuEmail author
  • Xiaoqin Ni
  • Peng Feng
  • Yu Wang


Osteoarthritis (OA), a type of joint diseases, could result in breakdown of joint cartilage and underlying bone. Accumulating evidences suggested that long non-coding RNAs play important roles in OA progression. However, the underlying mechanism of H19 in OA is still not fully explored. The expression levels of H19 and miR-106a-5p in OA samples from patients or cultured chondrocytes were examined by quantitative real time polymerase chain reaction. Cell proliferation and apoptosis were analysed by MTT assay and flow cytometry, respectively. Western blotting was employed to detect the expression levels of PCNA, CyclinD1, Caspase 3 and Cleaved Caspase 3. StarBase database, luciferase assay and RNA immunoprecipitation were introduced to confirm the relationship between H19 and miR-106a-5p. The correlation of H19 and miR-106a-5p was analysed by Spearman rank analysis. H19 expression was upregulated, while miR-106a-5p level was downregulated in OA samples and IL-1β-treated chondrocytes. H19 overexpression inhibited the proliferation and induced apoptosis in IL-1β-treated chondrocytes, while H19 knockdown induced the opposite effect. Luciferase and RIP assay demonstrated that miR-106a-5p was a direct target of H19. miR-106a-5p overexpression led to proliferation promotion and apoptosis inhibition in chondrocytes treated by IL-1β and it reversed the effect of H19 addition. We conclude that H19 could regulate proliferation and apoptosis of chondrocytes treated by IL-1β in OA via sponging miR-106a-5p.


Apoptosis H19 miR-106a-5p osteoarthritis proliferation 



  1. Abramson SB 2004 Inflammation in osteoarthritis. J. Rheumatol. Suppl. 70 70–76PubMedGoogle Scholar
  2. Adams CS and Jr HW 1998 Chondrocyte apoptosis increases with age in the articular cartilage of adult animals. Anat. Rec. 250 418–425PubMedCrossRefGoogle Scholar
  3. Aigner T, Hemmel M, Neureiter D, Gebhard PM, Zeiler G, Kirchner T and Mckenna L 2010 Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartil. Arthritis Rheumatism 44 1304–1312CrossRefGoogle Scholar
  4. Andreoli TE 1999 The Apoptotic syndromes - a basic biological phenomenon with wide ranging implications in tissue kinetics. Am. J. Med. 107 488PubMedCrossRefGoogle Scholar
  5. Benito MJ, Veale DJ, Fitzgerald O, Wb VDB and Bresnihan B 2005 Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 64 1263–1267PubMedPubMedCentralCrossRefGoogle Scholar
  6. Brannan CI, Dees EC, Ingram RS and Tilghman SM 1990 The product of the H19 gene may function as an RNA. Mol. Cell Biol. 10 28–36PubMedPubMedCentralCrossRefGoogle Scholar
  7. Brunner AL, Beck AH, Edris B, Sweeney RT, Zhu SX, Li R, Montgomery K, Varma S, et al. 2012 Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers. Genome Biol. 13 R75PubMedPubMedCentralCrossRefGoogle Scholar
  8. Cao L, Zhang Z, Li Y, Zhao P and Chen Y 2019 LncRNA H19/miR-let-7 axis participates in the regulation of ox-LDL-induced endothelial cell injury via targeting periostin. Int. Immunopharmacol. 72 496–503PubMedCrossRefGoogle Scholar
  9. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A and Bozzoni I 2011 A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147 358–369PubMedPubMedCentralCrossRefGoogle Scholar
  10. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, and March L 2014 The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73 1323–1330PubMedCrossRefGoogle Scholar
  11. Fadeel B and Orrenius S 2005 Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med. 258 479–517PubMedCrossRefPubMedCentralGoogle Scholar
  12. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, Kington RS, Lane NE, Nevitt MC, Zhang Y, Sowers M, McAlindon T, Spector TD, Poole AR, Yanovski SZ, Ateshian G, Sharma L, Buckwalter JA, Brandt KD and Fries JF 2000 Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann. Intern. Med. 133 635–646PubMedCrossRefPubMedCentralGoogle Scholar
  13. Feng J, Bi C, Clark BS, Mady R, Shah P and Kohtz JD 2006 The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20 1470–1484PubMedPubMedCentralCrossRefGoogle Scholar
  14. Gan L, Lv L and Liao S 2019 Long non‑coding RNA H19 regulates cell growth and metastasis via the miR‑22‑3p/Snail1 axis in gastric cancer. Int. J. Oncol. 54 2157–2168PubMedPubMedCentralGoogle Scholar
  15. Geisler S and Coller J 2013 RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mole Cell Biol. 14 699–712CrossRefGoogle Scholar
  16. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H and Carr AJ 2015 Osteoarthritis. Lancet 386 376–387PubMedPubMedCentralGoogle Scholar
  17. Gong C and Maquat LE 2011 lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470 284–288PubMedPubMedCentralCrossRefGoogle Scholar
  18. Häcker G 2000 The morphology of apoptosis. Cell Tissue Res. 301 5–17PubMedCrossRefPubMedCentralGoogle Scholar
  19. Heraud F, Heraud A and Harmand MF 2000 Apoptosis in normal and osteoarthritic human articular cartilage. Ann. Rheum. Dis. 59 959–965PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hu Y, Li S and Zou Y 2019 Knockdown of LncRNA H19 Relieves LPS-Induced Damage by Modulating miR-130a in Osteoarthritis. Yonsei Med. J. 60 381–388PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hua Q, Lv X, Gu X, Chen Y, Chu H, Du M, Gong W, Wang M and Zhang Z 2016 Genetic variants in lncRNA H19 are associated with the risk of bladder cancer in a Chinese population. Mutagenesis 31 531–538PubMedCrossRefGoogle Scholar
  22. Hunter DJ and Bierma-Zeinstra S 2019 Osteoarthritis. Lancet 393 1745–1759PubMedGoogle Scholar
  23. Ji Q, Qi D, Xu X, Xu Y, Goodman SB, Kang L, Song Q, Fan Z, Maloney WJ and Wang Y 2018 Cryptotanshinone protects cartilage against developing osteoarthritis through the miR-106a-5p/GLIS3 axis. Mol. Ther. Nucleic Acids 11 170–179PubMedPubMedCentralCrossRefGoogle Scholar
  24. Li H, Yu B, Li J, Su L, Yan M, Zhu Z and Liu B 2014 Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 5 2318–2329PubMedPubMedCentralGoogle Scholar
  25. Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan CC, Zhang JF and Waye MM 2015 The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget 6 22513–22525PubMedPubMedCentralGoogle Scholar
  26. Liu Q, Hu X, Zhang X, Dai L, Duan X, Zhou C and Ao Y 2016 The TMSB4 Pseudogene LncRNA Functions as a Competing Endogenous RNA to Promote Cartilage Degradation in Human Osteoarthritis. Mol. Ther. 24 1726–1733 CrossRefGoogle Scholar
  27. Ma B, Zhong L, van Blitterswijk CA, Post JN and Karperien M 2013 T cell factor 4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating nuclear factor κB signaling. J. Biol. Chem. 288 17552–17558PubMedPubMedCentralCrossRefGoogle Scholar
  28. Mobasheri A, Rayman MP, Gualillo O, Sellam J, van der Kraan P and Fearon U 2017 The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13 302–311PubMedCrossRefGoogle Scholar
  29. Muir H 1995 The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 17 1039–1048PubMedCrossRefGoogle Scholar
  30. Ng SY, Bogu G, Soh BS and Stanton L 2013 The long noncoding RNA RMST Interacts with SOX2 to regulate neurogenesis. Mol. Cell 51 349–359PubMedCrossRefGoogle Scholar
  31. Pearson MJ and Jones SW 2016 Long noncoding RNAs in the regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis. Arthritis Rheumatol. 68 2575–2583PubMedPubMedCentralCrossRefGoogle Scholar
  32. Ponting CP, Oliver PL and Reik W 2009 Evolution and functions of long noncoding RNAs. Cell 136 629–641PubMedCrossRefGoogle Scholar
  33. Salmena L, Poliseno L, Tay Y, Kats L and Pandolfi PP 2011 A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146 353–358PubMedPubMedCentralCrossRefGoogle Scholar
  34. Shen H, Wang Y, Shi W, Sun G, Hong L and Zhang Y 2018 LncRNA SNHG5/miR-26a/SOX2 signal axis enhances proliferation of chondrocyte in osteoarthritis. Acta. Biochim. Biophys. Sin. 50 191–198PubMedCrossRefGoogle Scholar
  35. Steck E, Boeuf S, Gabler J, Werth N, Schnatzer P, Diederichs S, Richter W 2012 Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions. J. Mol. Med. 90 1185–1195PubMedCrossRefPubMedCentralGoogle Scholar
  36. Sun H, Wang G, Peng Y, Zeng Y, Zhu QN, Li TL, Cai JQ, Zhou HH and Zhu YS 2015 H19 lncRNA mediates 17β-estradiol-induced cell proliferation in MCF-7 breast cancer cells. Oncol. Rep. 33 3045–3052PubMedCrossRefPubMedCentralGoogle Scholar
  37. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencower BJ, Prasanth SG and Prasanth KV 2010 The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating sr splicing factor phosphorylation. Mol. Cell 39 925–938PubMedPubMedCentralCrossRefGoogle Scholar
  38. Urban H and Little CB 2018 The role of fat and inflammation in the pathogenesis and management of osteoarthritis. Rheumatology 57 10–21CrossRefGoogle Scholar
  39. Wang G, Bu X, Zhang Y, Zhao X, Kong Y, Ma L, Niu S, Wu B and Meng C 2017 LncRNA-UCA1 enhances MMP-13 expression by inhibiting miR-204-5p in human chondrocytes. Oncotarget. 8 91281–91290Google Scholar
  40. Warner SC and Valdes AM 2017 Genetic association studies in osteoarthritis: is it fairytale? Curr. Opin. Rheumatol. 29 103–109PubMedCrossRefPubMedCentralGoogle Scholar
  41. Wu T, Qu L, He G, Tian L, Li L, Zhou H, Jin Q, Ren J, Wang Y, Wang J, Kan X, Liu M, Shen J, Guo M, Sun Y 2016 Regulation of laryngeal squamous cell cancer progression by the lncRNA H19/miR-148a-3p/DNMT1 axis. Oncotarget 7 11553–11566PubMedPubMedCentralGoogle Scholar
  42. Xu J and Xu Y 2017 The lncRNA MEG3 downregulation leads to osteoarthritis progression via miR-16/SMAD7 axis. Cell Biosci. 7 69PubMedPubMedCentralCrossRefGoogle Scholar
  43. Xue H, Tu Y, Ma T, Wen T, Yang T, Xue L, Cai M, Wang G, Guan M 2019 miR-93–5p attenuates IL-1β-induced chondrocyte apoptosis and cartilage degradation in osteoarthritis partially by targeting TCF4. Bone 123 129–136PubMedCrossRefPubMedCentralGoogle Scholar
  44. Zamli Z and Sharif M 2011 Chondrocyte apoptosis: a cause or consequence of osteoarthritis? Int. J. Rheum. Dis. 14 159–166PubMedCrossRefGoogle Scholar
  45. Zhang C, Zhang Z, Chang Z, Mao G, Hu S, Zeng A and Fu M 2019 miR-193b-5p regulates chondrocytes metabolism by directly targeting histone deacetylase 7 in interleukin-1β-induced osteoarthritis. J. Cell Chem. CrossRefGoogle Scholar
  46. Zhu M, Chen Q, Liu X, Sun Q, Zhao X, Deng R, Wang Y, Huang J, Xu M, Yan J and Yu J 2014 lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI. FEBS J. 281 3766–3775PubMedCrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  1. 1.Department of OrthopaedicsPeople’s Hospital of TongchuanTongchuanChina
  2. 2.Department of NursingYanan University Affiliated HospitalYananChina
  3. 3.Department of Respiratory MedicineYanan University Affiliated HospitalYananChina
  4. 4.Department of Medical Examination CenterPeople’s Hospital of TongchuanTongchuanChina

Personalised recommendations