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Long noncoding RNA lncAIS downregulation in mesenchymal stem cells is implicated in the pathogenesis of adolescent idiopathic scoliosis

Cell Death & Differentiation (2018) | Download Citation


Adolescent idiopathic scoliosis (AIS) is a complex, three dimensional deformity of the spine that commonly occurs in pubescent girls. Abnormal osteogenic differentiation of mesenchymal stem cells (MSCs) is implicated in the pathogenesis of AIS. However, the biological roles of long noncoding RNAs (lncRNAs) in the regulation of osteogenic differentiation of MSCs are unknown. Through microarray analyses of bone marrow (BM) MSCs from healthy donors and AIS patients, we identified 1483 differentially expressed lncRNAs in AIS BM-MSCs. We defined a novel lncAIS (gene symbol: ENST00000453347) is dramatically downregulated in AIS BM-MSCs. In normal BM-MSCs, lncAIS interacts with NF90 to promote HOXD8 mRNA stability that enhances RUNX2 transcription in BM-MSCs, leading to osteogenic differentiation of normal BM-MSCs. By contrast, lncAIS downregualtion in AIS BM-MSCs cannot recruit NF90 and abrogates HOXD8 mRNA stability, which impedes RUNX2 transcription for osteogenic differentiation. Thereby lncAIS downregualtion in BM-MSCs suppresses osteogenic differentiation that is implicated in the pathogenesis of AIS.

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  1. 1.

    Weinstein SL, Dolan LA, Cheng JC, Danielsson A, Morcuende JA. Adolescent idiopathic scoliosis. Lancet. 2008;371:1527–37.

  2. 2.

    Cheng JC, Castelein RM, Chu WC, Danielsson AJ, Dobbs MB, Grivas TB, et al. Adolescent idiopathic scoliosis. Nat Rev Dis Prim. 2015;1:30.

  3. 3.

    Lou EH, Hill DL, Raso JV, Moreau M, Hedden D. How quantity and quality of brace wear affect the brace treatment outcomes for AIS. Eur Spine J. 2016;25:495–9.

  4. 4.

    Sun W, Zhou J, Sun M, Qin X, Qiu Y, Zhu Z, et al. Low body mass index can be predictive of bracing failure in patients with adolescent idiopathic scoliosis: a retrospective study. Eur Spine J. 2017;26:1665–9.

  5. 5.

    Bartley CE, Yaszay B, Bastrom TP, Shah SA, Lonner BS, Asghar J, et al. Perioperative and delayed major complications following surgical treatment of adolescent idiopathic scoliosis. J Bone Jt Surg Am. 2017;99:1206–12.

  6. 6.

    Pourabbas Tahvildari B, Erfani MA, Nouraei H, Sadeghian M. Evaluation of bone mineral status in adolescent idiopathic scoliosis. Clin Orthop Surg. 2014;6:180–4.

  7. 7.

    Yim AP, Yeung HY, Hung VW, Lee KM, Lam TP, Ng BK, et al. Abnormal skeletal growth patterns in adolescent idiopathic scoliosis--a longitudinal study until skeletal maturity. Spine. 2012;37:E1148–1154.

  8. 8.

    Burner WL 3rd, Badger VM, Sherman FC. Osteoporosis and acquired back deformities. J Pediatr Orthop. 1982;2:383–5.

  9. 9.

    Ishida K, Aota Y, Mitsugi N, Kono M, Higashi T, Kawai T, et al. Relationship between bone density and bone metabolism in adolescent idiopathic scoliosis. Scoliosis. 2015;10:19.

  10. 10.

    Li XF, Li H, Liu ZD, Dai LY. Low bone mineral status in adolescent idiopathic scoliosis. Eur Spine J. 2008;17:1431–40.

  11. 11.

    Yip BH, Yu FW, Wang Z, Hung VW, Lam TP, Ng BK, et al. Prognostic value of bone mineral density on curve progression: a longitudinal cohort study of 513 girls with adolescent idiopathic scoliosis. Sci Rep. 2016;6:39220.

  12. 12.

    Cheng JC, Hung VW, Lee WT, Yeung HY, Lam TP, Ng BK, et al. Persistent osteopenia in adolescent idiopathic scoliosis--longitudinal monitoring of bone mineral density until skeletal maturity. Stud Health Technol Inform. 2006;123:47–51.

  13. 13.

    Garg P, Mazur MM, Buck AC, Wandtke ME, Liu J, Ebraheim NA. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg. 2017;9:13–19.

  14. 14.

    Gibon E, Lu L, Goodman SBAging. inflammation, stem cells, and bone healing. Stem Cell Res & Ther. 2016;7:44.

  15. 15.

    Wang X, Wang Y, Gou W, Lu Q, Peng J, Lu S. Role of mesenchymal stem cells in bone regeneration and fracture repair: a review. Int Orthop. 2013;37:2491–8.

  16. 16.

    Qin Y, Guan J, Zhang C. Mesenchymal stem cells: mechanisms and role in bone regeneration. Postgrad Med J. 2014;90:643–7.

  17. 17.

    Zhuang Q, Li J, Wu Z, Zhang J, Sun W, Li T, et al. Differential proteome analysis of bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients. PLoS ONE. 2011;6:0018834.

  18. 18.

    Park WW, Suh KT, Kim JI, Kim SJ, Lee JS. Decreased osteogenic differentiation of mesenchymal stem cells and reduced bone mineral density in patients with adolescent idiopathic scoliosis. Eur Spine J. 2009;18:1920–6.

  19. 19.

    Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.

  20. 20.

    Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17:47–62.

  21. 21.

    Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.

  22. 22.

    Zhu P, Wang Y, Huang G, Ye B, Liu B, Wu J, et al. lnc-beta-Catm elicits EZH2-dependent beta-catenin stabilization and sustains liver CSC self-renewal. Nat Struct Mol Biol. 2016;23:631–9.

  23. 23.

    Zhu P, Wang Y, Wu J, Huang G, Liu B, Ye B, et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat Commun. 2016;7:13608.

  24. 24.

    Luo S, Lu JY, Liu L, Yin Y, Chen C, Han X, et al. Divergent lncRNAs regulate gene expression and lineage differentiation in pluripotent cells. Cell Stem Cell. 2016;18:637–52.

  25. 25.

    Anderson KM, Anderson DM, McAnally JR, Shelton JM, Bassel-Duby R, Olson EN. Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature. 2016;539:433–6.

  26. 26.

    Jiang W, Huang H, Ding L, Zhu P, Saiyin H, Ji G, et al. Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability. Oncogene. 2015;34:4460–70.

  27. 27.

    Song D, Huang H, Wang J, Zhao Y, Hu X, He F, et al. NF90 regulates PARP1 mRNA stability in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;488:211–7.

  28. 28.

    Thiagarajan L, Abu-Awwad HAM, Dixon JE. Osteogenic Programming of Human Mesenchymal Stem Cells with Highly Efficient Intracellular Delivery of RUNX2. Stem Cells Transl Med. 2017;6:2146–59.

  29. 29.

    Zhuang Q, Mao W, Xu P, Li H, Sun Z, Li S, et al. Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopathic Scoliosis Patients by Microarray and Integrated Gene Network Analysis. Spine. 2016;41:840–55.

  30. 30.

    Chen C, Xu C, Zhou T, Gao B, Zhou H, Chen C, et al. Abnormal osteogenic and chondrogenic differentiation of human mesenchymal stem cells from patients with adolescent idiopathic scoliosis in response to melatonin. Mol Med Rep. 2016;14:1201–9.

  31. 31.

    Song XX, Jin LY, Li XF, Qian L, Shen HX, Liu ZD, et al. Effects of Low Bone Mineral Status on Biomechanical Characteristics in Idiopathic Scoliotic Spinal Deformity. World neurosurg. 2017;110:e321–9.

  32. 32.

    Akazawa T, Kotani T, Sakuma T, Katogi T, Minami S, Niki H, et al. Bone mineral density and physical performance of female patients 27 years or longer after surgery for adolescent idiopathicscoliosis. Asian Spine J. 2017;11:780–6.

  33. 33.

    Hung VW, Qin L, Cheung CS, Lam TP, Ng BK, Tse YK, et al. Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Jt Surg Am. 2005;87:2709–16.

  34. 34.

    Noshchenko A, Hoffecker L, Lindley EM, Burger EL, Cain CM, Patel VV, et al. Predictors of spine deformity progression in adolescent idiopathic scoliosis: a systematic review with meta-analysis. World J Orthop. 2015;6:537–58.

  35. 35.

    Flynn RA, Chang HY. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 2014;14:752–61.

  36. 36.

    Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

  37. 37.

    Liu XY, Wang L, Yu B, Zhuang QY, Wang YP. Expression signatures of long noncoding RNAs in adolescent idiopathic Scoliosis. Biomed Res Int. 2015;2015:276049.

  38. 38.

    Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.

  39. 39.

    Kao PN, Chen L, Brock G, Ng J, Kenny J, Smith AJ, et al. Cloning and expression of cyclosporin A- and FK506-sensitive nuclear factor of activated T-cells: NF45 and NF90. J Biol Chem. 1994;269:20691–9.

  40. 40.

    Shi L, Godfrey WR, Lin J, Zhao G, Kao PN. NF90 regulates inducible IL-2 gene expression in T cells. J Exp Med. 2007;204:971–7.

  41. 41.

    Reichman TW, Parrott AM, Fierro-Monti I, Caron DJ, Kao PN, Lee CG, et al. Selective regulation of gene expression by nuclear factor 110, a member of the NF90 family of double-stranded RNA-binding proteins. J Mol Biol. 2003;332:85–98.

  42. 42.

    Kiesler P, Haynes PA, Shi L, Kao PN, Wysocki VH, Vercelli D. NF45 and NF90 regulate HS4-dependent interleukin-13 transcription in T cells. J Biol Chem. 2010;285:8256–67.

  43. 43.

    Castella S, Bernard R, Corno M, Fradin A, Larcher JC. Ilf3 and NF90 functions in RNA biology. Wiley Interdiscip Rev RNA. 2015;6:243–56.

  44. 44.

    Kuwano Y, Kim HH, Abdelmohsen K, Pullmann R Jr, Martindale JL, et al. MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90. Mol Cell Biol. 2008;28:4562–75.

  45. 45.

    Vumbaca F, Phoenix KN, Rodriguez-Pinto D, Han DK, Claffey KP. Double-stranded RNA-binding protein regulates vascular endothelial growth factor mRNA stability, translation, and breast cancer angiogenesis. Mol Cell Biol. 2008;28:772–83.

  46. 46.

    Pei Y, Zhu P, Dang Y, Wu J, Yang X, Wan B, et al. Nuclear export of NF90 to stabilize IL-2 mRNA is mediated by AKT-dependent phosphorylation at Ser647 in response to CD28 costimulation. J Immunol. 2008;180:222–9.

  47. 47.

    Sakamoto S, Aoki K, Higuchi T, Todaka H, Morisawa K, Tamaki N, et al. The NF90-NF45 complex functions as a negative regulator in the microRNA processing pathway. Mol Cell Biol. 2009;29:3754–69.

  48. 48.

    Krumlauf R. Hox genes in vertebrate development. Cell. 1994;78:191–201.

  49. 49.

    Wang KC, Helms JA, Chang HY. Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Trends Cell Biol. 2009;19:268–75.

  50. 50.

    Klein D, Benchellal M, Kleff V, Jakob HG, Ergun S. Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells. Sci Rep. 2013;3:2178.

  51. 51.

    Akam M. Hox genes: from master genes to micromanagers. Curr Biol. 1998;8:R676–8.

  52. 52.

    Ackema KB, Charite J. Mesenchymal stem cells from different organs are characterized by distinct topographic Hox codes. Stem Cells Dev. 2008;17:979–91.

  53. 53.

    Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA. 2002;99:12877–82.

  54. 54.

    Xu YX, Xu B, Wu CL, Wu Y, Tong PJ, Xiao LW. Dynamic expression of DKK1 protein in the process whereby Epimedium-derived flavonoids up-regulate osteogenic and down-regulate adipogenic differentiation of bone marrow stromal cells in ovariectomized rats. Orthop Surg. 2011;3:119–26.

  55. 55.

    Ma XL, Liu ZP, Ma JX, Han C, Zang JC. Dynamic expression of Runx2, Osterix and AJ18 in the femoral head of steroid-induced osteonecrosis in rats. Orthop Surg. 2010;2:278–84.

  56. 56.

    Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64.

  57. 57.

    Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science. 2000;289:1501–4.

  58. 58.

    Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89:747–54.

  59. 59.

    Wang WJ, Sun C, Liu Z, Sun X, Zhu F, Zhu ZZ, et al. Transcription factor Runx2 in the low bone mineral density of girls with adolescent idiopathic scoliosis. Orthop Surg. 2014;6:8–14.

  60. 60.

    Han P, Li W, Lin CH, Yang J, Shang C, Nuernberg ST, et al. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014;514:102–6.

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We thank Jing Li (Cnkingbio Company Ltd, Beijing, China) for technical support. We thank Peng Xue, Xiang Ding, Yan Teng, Yihui Xu, Junying Jia, Xudong Zhao and Xiaofei Guo for technical support. This work was supported by the National Natural Science Foundation of China (81272054, 81171673, 91640203), Beijing Talent Fund (2015000021223ZK27), Beijing Nova program Grant (2014A019), Beijing High-level Innovative Entrepreneurial Talent Fund, Beijing Natural Science Foundation (7181006). Peking Union Medical College Youth Fund, PUMC Nova program Grant of Chinese academy of medical sciences.

Author contributions

QZ, BY and SH designed and performed experiments; QZ and BY analyzed the data and wrote the paper; YD, RZ, JL, ZW, NL, YZ, HL, SW, and Y.Y. analyzed the data; JL, SL, and HZ performed some experiments; ZF organized, designed, and wrote the paper, and GQ and JZ initiated the study and analyzed the data.

Author information

Author notes

  1. These authors contributed equally: Qianyu Zhuang, Buqing Ye, Shangyi Hui.

  2. These authors contributed equally: Zusen Fan, Guixing Qiu, Jianguo Zhang.


  1. Department of Orthopedics, Peking Union Medical College Hospital, Beijing, P.R. China

    • Qianyu Zhuang
    • , Zhihong Wu
    • , Yanbin Zhang
    • , Shengru Wang
    • , Yang Yang
    • , Shugang Li
    • , Hong Zhao
    • , Guixing Qiu
    •  & Jianguo Zhang
  2. CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    • Buqing Ye
    • , Ying Du
    •  & Zusen Fan
  3. Department of Anesthesiolgy, Peking Union Medical College Hospital, Beijing, China

    • Shangyi Hui
  4. Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    • Robert Chunhua Zhao
    • , Jing Li
    • , Na Li
    •  & Hongling Li


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The authors declare that they have no conflict of interest.

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Correspondence to Zusen Fan or Jianguo Zhang.

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