Cellular and Molecular Life Sciences

, Volume 74, Issue 19, pp 3451–3465 | Cite as

Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair

  • Andrea LolliEmail author
  • Letizia Penolazzi
  • Roberto Narcisi
  • Gerjo J. V. M. van Osch
  • Roberta PivaEmail author


The field of cartilage repair has exponentially been growing over the past decade. Here, we discuss the possibility to achieve satisfactory regeneration of articular cartilage by means of human mesenchymal stem cells (hMSCs) depleted of anti-chondrogenic factors and implanted in the site of injury. Different types of molecules including transcription factors, transcriptional co-regulators, secreted proteins, and microRNAs have recently been identified as negative modulators of chondroprogenitor differentiation and chondrocyte function. We review the current knowledge about these molecules as potential targets for gene knockdown strategies using RNA interference (RNAi) tools that allow the specific suppression of gene function. The critical issues regarding the optimization of the gene silencing approach as well as the delivery strategies are discussed. We anticipate that further development of these techniques will lead to the generation of implantable hMSCs with enhanced potential to regenerate articular cartilage damaged by injury, disease, or aging.


Gene silencing RNA interference MicroRNA Cartilage repair Chondrogenesis Mesenchymal stem cells Anti-chondrogenic regulators 



Aminoacyl tRNA synthetase complex interacting multifunctional protein 1


Angiopoietin-like 4


Bone morphogenetic protein


Circular RNA


Extracellular matrix


Epithelial-to-mesenchymal transition


Extracellular signal-regulated kinase


Extracellular vesicle


Fibroblasts growth factor




Human mesenchymal stem cells


Insulin-like growth factor


Indian hedgehog


IkB kinase


C-Jun N-terminal kinase


Lysine demethylase 2A


Long non-coding RNA


Mitogen-activated protein kinase


Mandibular condylar cartilage


Mitogen-activated protein kinase


Matrix metalloproteinase






p53-Inducible ribonucleotide reductase






Prolyl hydroxylase domain-containing protein 2






Peptide nucleic acid


Quantum dot


RNA-induced silencing complex


RNA interference


Runt-related transcription factor 2


Short hairpin RNA


Short interfering RNA


SRY (sex determining region Y)-box


Transcription factor


Transforming growth factor


TGF-β induced factor homeobox 1


Vascular endothelial growth factor



A.L. is funded by the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska Curie Grant agreement No 642414. R.N. is supported by the VENI Grant by STW (13659). The authors are grateful to Dr. E. J. Farrell, Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, for English revision of the manuscript.


  1. 1.
    Musumeci G, Aiello FC, Szychlinska MA, Di Rosa M, Castrogiovanni P, Mobasheri A (2015) Osteoarthritis in the XXIst century: risk factors and behaviours that influence disease onset and progression. Int J Mol Sci 16(3):6093–6112CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Akkiraju H, Nohe A (2015) Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J Dev Biol 3(4):177–192CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brittberg M (2015) Cellular and acellular approaches for cartilage repair: a philosophical analysis. Cartilage 6(2 Suppl):4S–12SCrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Jayasuriya CT, Chen Y, Liu W, Chen Q (2016) The influence of tissue microenvironment on stem cell-based cartilage repair. Ann N Y Acad Sci 1383(1):21–33CrossRefPubMedGoogle Scholar
  5. 5.
    Yamasaki S, Mera H, Itokazu M, Hashimoto Y, Wakitani S (2014) Cartilage repair with autologous bone marrow mesenchymal stem cell transplantation: review of preclinical and clinical studies. Cartilage 5(4):196–202CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Li KC, Hu YC (2015) Cartilage tissue engineering: recent advances and perspectives from gene regulation/therapy. Adv Healthc Mater 4(7):948–968CrossRefPubMedGoogle Scholar
  7. 7.
    Fellows CR, Matta C, Zakany R, Khan IM, Mobasheri A (2016) Adipose, bone marrow and synovial joint-derived mesenchymal stem cells for cartilage repair. Front Genet 7:213CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Anz AW, Bapat A, Murrell WD (2016) Concepts in regenerative medicine: past, present, and future in articular cartilage treatment. J Clin Orthop Trauma 7(3):137–144CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    de Windt TS, Vonk LA, Slaper-Cortenbach IC, van den Broek MP, Nizak R, van Rijen MH, de Weger RA, Dhert WJ, Saris DB (2017) Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons. Stem Cells 35(1):256–264CrossRefPubMedGoogle Scholar
  10. 10.
    Baghaban Eslaminejad M, Malakooty Poor E (2014) Mesenchymal stem cells as a potent cell source for articular cartilage regeneration. World J Stem Cells 6(3):344–354CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Madry H, Cucchiarini M (2011) Clinical potential and challenges of using genetically modified cells for articular cartilage repair. Croat Med J 52(3):245–261CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kozhemyakina E, Lassar AB, Zelzer E (2015) A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development 142(5):817–831CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldring MB (2012) Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis 4(4):269–285CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Matta C, Mobasheri A (2014) Regulation of chondrogenesis by protein kinase C: emerging new roles in calcium signalling. Cell Signal 26(5):979–1000CrossRefPubMedGoogle Scholar
  15. 15.
    Topol L, Chen W, Song H, Day TF, Yang Y (2009) Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. J Biol Chem 284(5):3323–3333CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lefebvre V, Smits P (2005) Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res C Embryo Today 75(3):200–212CrossRefPubMedGoogle Scholar
  17. 17.
    Gibson TJ, Seiler M, Veitia RA (2013) The transience of transient overexpression. Nat Methods 10(8):715–721CrossRefPubMedGoogle Scholar
  18. 18.
    Gyorgy A, Del Vecchio D (2014) Limitations and trade-offs in gene expression due to competition for shared cellular resources. Proceedings of the 53rd IEEE Conference on Decision and Control:
  19. 19.
    Battistella M, Marsden PA (2015) Advances, nuances, and potential pitfalls when exploiting the therapeutic potential of RNA interference. Clin Pharmacol Ther 97(1):79–87CrossRefPubMedGoogle Scholar
  20. 20.
    Borna H, Imani S, Iman M, Jamalkandi S (2015) Therapeutic face of RNAi: in vivo challenges. Expert Opin Biol Ther 15(2):269–285CrossRefPubMedGoogle Scholar
  21. 21.
    Jeon SY, Park JS, Yang HN, Lim HJ, Yi SW, Park H, Park KH (2014) Co-delivery of Cbfa-1-targeting siRNA and SOX9 protein using PLGA nanoparticles to induce chondrogenesis of human mesenchymal stem cells. Biomaterials 35(28):8236–8248CrossRefPubMedGoogle Scholar
  22. 22.
    Diekman BO, Thakore PI, O’Connor SK, Willard VP, Brunger JM, Christoforou N, Leong KW, Gersbach CA, Guilak F (2015) Knockdown of the cell cycle inhibitor p21 enhances cartilage formation by induced pluripotent stem cells. Tissue Eng Part A 21(7–8):1261–1274CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ahn J, Kumar H, Cha BH, Park S, Arai Y, Han I, Park SG, Lee SH (2016) AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-beta signal. Cell Death Dis 7:e2099CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Umeda M, Terao F, Miyazaki K, Yoshizaki K, Takahashi I (2015) MicroRNA-200a regulates the development of mandibular condylar cartilage. J Dent Res 94(6):795–802CrossRefPubMedGoogle Scholar
  25. 25.
    Liew A, Andre FM, Lesueur LL, De Menorval MA, O’Brien T, Mir LM (2013) Robust, efficient, and practical electrogene transfer method for human mesenchymal stem cells using square electric pulses. Hum Gene Ther Methods 24(5):289–297CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    King WJ, Kouris NA, Choi S, Ogle BM, Murphy WL (2012) Environmental parameters influence non-viral transfection of human mesenchymal stem cells for tissue engineering applications. Cell Tissue Res 347(3):689–699CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yu X, Murphy WL (2014) 3-D scaffold platform for optimized non-viral transfection of multipotent stem cells. J Mater Chem B Mater Biol Med 2(46):8186–8193CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cucchiarini M, Madry H (2014) Use of tissue engineering strategies to repair joint tissues in osteoarthritis: viral gene transfer approaches. Curr Rheumatol Rep 16(10):449CrossRefPubMedGoogle Scholar
  29. 29.
    Raisin S, Belamie E, Morille M (2016) Non-viral gene activated matrices for mesenchymal stem cells based tissue engineering of bone and cartilage. Biomaterials 104:223–237CrossRefPubMedGoogle Scholar
  30. 30.
    Abdul Halim NS, Fakiruddin KS, Ali SA, Yahaya BH (2014) A comparative study of non-viral gene delivery techniques to human adipose-derived mesenchymal stem cell. Int J Mol Sci 15(9):15044–15060CrossRefPubMedGoogle Scholar
  31. 31.
    Mencia Castano I, Curtin CM, Shaw G, Murphy JM, Duffy GP, O’Brien FJ (2015) A novel collagen-nanohydroxyapatite microRNA-activated scaffold for tissue engineering applications capable of efficient delivery of both miR-mimics and antagomiRs to human mesenchymal stem cells. J Control Release 200:42–51CrossRefPubMedGoogle Scholar
  32. 32.
    Lolli A, Narcisi R, Lambertini E, Penolazzi L, Angelozzi M, Kops N, Gasparini S, van Osch GJ, Piva R (2016) Silencing of antichondrogenic microRNA-221 in human mesenchymal stem cells promotes cartilage repair in vivo. Stem Cells 34(7):1801–1811CrossRefPubMedGoogle Scholar
  33. 33.
    Li Z, Rana TM (2014) Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13(8):622–638CrossRefPubMedGoogle Scholar
  34. 34.
    Mokhtarzadeh A, Alibakhshi A, Hashemi M, Hejazi M, Hosseini V, de la Guardia M, Ramezani M (2017) Biodegradable nano-polymers as delivery vehicles for therapeutic small non-coding ribonucleic acids. J Control Release 245:116–126CrossRefPubMedGoogle Scholar
  35. 35.
    Pi Y, Zhang X, Shao Z, Zhao F, Hu X, Ao Y (2015) Intra-articular delivery of anti-Hif-2alpha siRNA by chondrocyte-homing nanoparticles to prevent cartilage degeneration in arthritic mice. Gene Ther 22(6):439–448CrossRefPubMedGoogle Scholar
  36. 36.
    Ollitrault D, Legendre F, Drougard C, Briand M, Benateau H, Goux D, Chajra H, Poulain L, Hartmann D, Vivien D, Shridhar V, Baldi A, Mallein-Gerin F, Boumediene K, Demoor M, Galera P (2015) BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes. Tissue Eng Part C Methods 21(2):133–147CrossRefPubMedGoogle Scholar
  37. 37.
    Mathieu M, Iampietro M, Chuchana P, Guerit D, Djouad F, Noel D, Jorgensen C (2014) Involvement of angiopoietin-like 4 in matrix remodeling during chondrogenic differentiation of mesenchymal stem cells. J Biol Chem 289(12):8402–8412CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chang T, Xie J, Li H, Li D, Liu P, Hu Y (2016) MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9. Cell Prolif 49(2):207–218CrossRefPubMedGoogle Scholar
  39. 39.
    Monteiro N, Martins A, Reis RL, Neves NM (2014) Liposomes in tissue engineering and regenerative medicine. J R Soc Interface 11(101):20140459CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Knudsen KB, Northeved H, Kumar PE, Permin A, Gjetting T, Andresen TL, Larsen S, Wegener KM, Lykkesfeldt J, Jantzen K, Loft S, Moller P, Roursgaard M (2015) In vivo toxicity of cationic micelles and liposomes. Nanomedicine 11(2):467–477CrossRefPubMedGoogle Scholar
  41. 41.
    Cui ZK, Fan J, Kim S, Bezouglaia O, Fartash A, Wu BM, Aghaloo T, Lee M (2015) Delivery of siRNA via cationic Sterosomes to enhance osteogenic differentiation of mesenchymal stem cells. J Control Release 217:42–52CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jeon SY, Park JS, Yang HN, Woo DG, Park KH (2012) Co-delivery of SOX9 genes and anti-Cbfa-1 siRNA coated onto PLGA nanoparticles for chondrogenesis of human MSCs. Biomaterials 33(17):4413–4423CrossRefPubMedGoogle Scholar
  43. 43.
    Yan H, Duan X, Pan H, Holguin N, Rai MF, Akk A, Springer LE, Wickline SA, Sandell LJ, Pham CT (2016) Suppression of NF-kappaB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci USA 113(41):E6199–E6208CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rosenthal SJ, Chang JC, Kovtun O, McBride JR, Tomlinson ID (2011) Biocompatible quantum dots for biological applications. Chem Biol 18(1):10–24CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Xu J, Li J, Lin S, Wu T, Huang H, Zhang K, Sun Y, Yeung KW, Li G, Bian L (2016) Nanocarrier-mediated codelivery of small molecular drugs and siRNA to enhance chondrogenic differentiation and suppress hypertrophy of human mesenchymal stem cells. Adv Funct Mater 26(15):2643–2672CrossRefGoogle Scholar
  46. 46.
    Wu Y, Zhou B, Xu F, Wang X, Liu G, Zheng L, Zhao J, Zhang X (2016) Functional quantum dot-siRNA nanoplexes to regulate chondrogenic differentiation of mesenchymal stem cells. Acta Biomater 46:165–176CrossRefPubMedGoogle Scholar
  47. 47.
    Lamichhane TN, Raiker RS, Jay SM (2015) Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery. Mol Pharm 12(10):3650–3657CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Banizs AB, Huang T, Dryden K, Berr SS, Stone JR, Nakamoto RK, Shi W, He J (2014) In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery. Int J Nanomedicine 9:4223–4230PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, Letko Khait N, Lupu-Haber Y, Fliman M, Schoen BW, Kaneti G, Machluf M (2016) Nanoghosts as a novel natural nonviral gene delivery platform safely targeting multiple cancers. Nano Lett 16(3):1574–1582CrossRefPubMedGoogle Scholar
  50. 50.
    Toledano Furman NE, Lupu-Haber Y, Bronshtein T, Kaneti L, Letko N, Weinstein E, Baruch L, Machluf M (2013) Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett 13(7):3248–3255CrossRefPubMedGoogle Scholar
  51. 51.
    Green JD, Tollemar V, Dougherty M, Yan Z, Yin L, Ye J, Collier Z, Mohammed MK, Haydon RC, Luu HH, Kang R, Lee MJ, Ho SH, He TC, Shi LL, Athiviraham A (2015) Multifaceted signaling regulators of chondrogenesis: implications in cartilage regeneration and tissue engineering. Genes Dis 2(4):307–327CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G (2001) Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 15(4):467–481CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Koelling S, Kruegel J, Irmer M, Path JR, Sadowski B, Miro X, Miosge N (2009) Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell 4(4):324–335CrossRefPubMedGoogle Scholar
  54. 54.
    Schminke B, Muhammad H, Bode C, Sadowski B, Gerter R, Gersdorff N, Burgers R, Monsonego-Ornan E, Rosen V, Miosge N (2014) A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint. Cell Mol Life Sci 71(6):1081–1096CrossRefPubMedGoogle Scholar
  55. 55.
    Lorda-Diez CI, Montero JA, Martinez-Cue C, Garcia-Porrero JA, Hurle JM (2009) Transforming growth factors beta coordinate cartilage and tendon differentiation in the developing limb mesenchyme. J Biol Chem 284(43):29988–29996CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Chen L, Jiang C, Tiwari SR, Shrestha A, Xu P, Liang W, Sun Y, He S, Cheng B (2015) TGIF1 gene silencing in tendon-derived stem cells improves the tendon-to-bone insertion site regeneration. Cell Physiol Biochem 37(6):2101–2114CrossRefPubMedGoogle Scholar
  57. 57.
    Li J, Chen L, Sun L, Chen H, Sun Y, Jiang C, Cheng B (2015) Silencing of TGIF1 in bone mesenchymal stem cells applied to the post-operative rotator cuff improves both functional and histologic outcomes. J Mol Histol 46(3):241–249CrossRefPubMedGoogle Scholar
  58. 58.
    Bobick BE, Cobb J (2012) Shox2 regulates progression through chondrogenesis in the mouse proximal limb. J Cell Sci 125(Pt 24):6071–6083CrossRefPubMedGoogle Scholar
  59. 59.
    Tian Y, Xu Y, Fu Q, Chang M, Wang Y, Shang X, Wan C, Marymont JV, Dong Y (2015) Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1. Mol Cell Endocrinol 403:30–38CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Lolli A, Lambertini E, Penolazzi L, Angelozzi M, Morganti C, Franceschetti T, Pelucchi S, Gambari R, Piva R (2014) Pro-chondrogenic effect of miR-221 and slug depletion in human MSCs. Stem Cell Rev 10(6):841–855CrossRefPubMedGoogle Scholar
  61. 61.
    Lisignoli G, Manferdini C, Lambertini E, Zini N, Angelozzi M, Gabusi E, Gambari L, Penolazzi L, Lolli A, Facchini A, Piva R (2014) Chondrogenic potential of Slug-depleted human mesenchymal stem cells. Tissue Eng Part A 20(19–20):2795–2805CrossRefPubMedGoogle Scholar
  62. 62.
    Beier F (2005) Cell-cycle control and the cartilage growth plate. J Cell Physiol 202(1):1–8CrossRefPubMedGoogle Scholar
  63. 63.
    Zhong W, Li Y, Li L, Zhang W, Wang S, Zheng X (2013) YAP-mediated regulation of the chondrogenic phenotype in response to matrix elasticity. J Mol Histol 44(5):587–595CrossRefPubMedGoogle Scholar
  64. 64.
    Zhou HW, Lou SQ, Zhang K (2004) Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro. Rheumatology (Oxford) 43(5):555–568CrossRefGoogle Scholar
  65. 65.
    Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, Ducy P, Rahman MU, Flavell RA, Gravallese EM, Oettgen P, Libermann TA, Goldring MB (2005) A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem 280(46):38544–38555CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bobick BE, Matsche AI, Chen FH, Tuan RS (2010) The ERK5 and ERK1/2 signaling pathways play opposing regulatory roles during chondrogenesis of adult human bone marrow-derived multipotent progenitor cells. J Cell Physiol 224(1):178–186PubMedGoogle Scholar
  67. 67.
    Olivotto E, Borzi RM, Vitellozzi R, Pagani S, Facchini A, Battistelli M, Penzo M, Li X, Flamigni F, Li J, Falcieri E, Facchini A, Marcu KB (2008) Differential requirements for IKKalpha and IKKbeta in the differentiation of primary human osteoarthritic chondrocytes. Arthritis Rheum 58(1):227–239CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Kawakita K, Nishiyama T, Fujishiro T, Hayashi S, Kanzaki N, Hashimoto S, Takebe K, Iwasa K, Sakata S, Nishida K, Kuroda R, Kurosaka M (2012) Akt phosphorylation in human chondrocytes is regulated by p53R2 in response to mechanical stress. Osteoarthritis Cartilage 20(12):1603–1609CrossRefPubMedGoogle Scholar
  69. 69.
    Thoms BL, Murphy CL (2010) Inhibition of hypoxia-inducible factor-targeting prolyl hydroxylase domain-containing protein 2 (PHD2) enhances matrix synthesis by human chondrocytes. J Biol Chem 285(27):20472–20480CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Dong R, Yao R, Du J, Wang S, Fan Z (2013) Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla. Exp Cell Res 319(18):2874–2882CrossRefPubMedGoogle Scholar
  71. 71.
    McDermott BT, Ellis S, Bou-Gharios G, Clegg PD, Tew SR (2016) RNA binding proteins regulate anabolic and catabolic gene expression in chondrocytes. Osteoarthritis Cartilage 24(7):1263–1273CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Zeng G, Cui X, Liu Z, Zhao H, Zheng X, Zhang B, Xia C (2014) Disruption of phosphoinositide-specific phospholipases Cgamma1 contributes to extracellular matrix synthesis of human osteoarthritis chondrocytes. Int J Mol Sci 15(8):13236–13246CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Karlsen TA, Jakobsen RB, Mikkelsen TS, Brinchmann JE (2014) microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev 23(3):290–304CrossRefPubMedGoogle Scholar
  74. 74.
    Song L, Webb NE, Song Y, Tuan RS (2006) Identification and functional analysis of candidate genes regulating mesenchymal stem cell self-renewal and multipotency. Stem Cells 24(7):1707–1718CrossRefPubMedGoogle Scholar
  75. 75.
    Hattori T, Kishino T, Stephen S, Eberspaecher H, Maki S, Takigawa M, de Crombrugghe B, Yasuda H (2013) E6-AP/UBE3A protein acts as a ubiquitin ligase toward SOX9 protein. J Biol Chem 288(49):35138–35148CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Chen E, Tang MK, Yao Y, Yau WW, Lo LM, Yang X, Chui YL, Chan J, Lee KK (2013) Silencing BRE expression in human umbilical cord perivascular (HUCPV) progenitor cells accelerates osteogenic and chondrogenic differentiation. PLoS One 8(7):e67896CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhang F, Yao Y, Su K, Fang Y, Citra F, Wang DA (2015) Co-transduction of lentiviral and adenoviral vectors for co-delivery of growth factor and shRNA genes in mesenchymal stem cells-based chondrogenic system. J Tissue Eng Regen Med 9(9):1036–1045CrossRefPubMedGoogle Scholar
  78. 78.
    Twomey JD, Thakore PI, Hartman DA, Myers EG, Hsieh AH (2014) Roles of type VI collagen and decorin in human mesenchymal stem cell biophysics during chondrogenic differentiation. Eur Cell Mater 27:237–250CrossRefPubMedGoogle Scholar
  79. 79.
    Kafienah W, Cheung FL, Sims T, Martin I, Miot S, Von Ruhland C, Roughley PJ, Hollander AP (2008) Lumican inhibits collagen deposition in tissue engineered cartilage. Matrix Biol 27(6):526–534CrossRefPubMedGoogle Scholar
  80. 80.
    Nakajima M, Kizawa H, Saitoh M, Kou I, Miyazono K, Ikegawa S (2007) Mechanisms for asporin function and regulation in articular cartilage. J Biol Chem 282(44):32185–32192CrossRefPubMedGoogle Scholar
  81. 81.
    Wang ZH, Yang ZQ, He XJ, Kamal BE, Xing Z (2010) Lentivirus-mediated knockdown of aggrecanase-1 and -2 promotes chondrocyte-engineered cartilage formation in vitro. Biotechnol Bioeng 107(4):730–736CrossRefPubMedGoogle Scholar
  82. 82.
    Jin EJ, Choi YA, Kyun Park E, Bang OS, Kang SS (2007) MMP-2 functions as a negative regulator of chondrogenic cell condensation via down-regulation of the FAK-integrin beta1 interaction. Dev Biol 308(2):474–484CrossRefPubMedGoogle Scholar
  83. 83.
    Zhang X, Crawford R, Xiao Y (2016) Inhibition of vascular endothelial growth factor with shRNA in chondrocytes ameliorates osteoarthritis. J Mol Med (Berl) 94(7):787–798CrossRefGoogle Scholar
  84. 84.
    Wei F, Zhou J, Wei X, Zhang J, Fleming BC, Terek R, Pei M, Chen Q, Liu T, Wei L (2012) Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthritis Cartilage 20(7):755–763CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Morigele M, Shao Z, Zhang Z, Kaige M, Zhang Y, Qiang W, Yang S (2013) TGF-beta1 induces a nucleus pulposus-like phenotype in Notch 1 knockdown rabbit bone marrow mesenchymal stem cells. Cell Biol Int 37(8):820–825CrossRefPubMedGoogle Scholar
  86. 86.
    Ryu JH, Chun JS (2006) Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes. J Biol Chem 281(31):22039–22047CrossRefPubMedGoogle Scholar
  87. 87.
    Takahashi T, Ogasawara T, Asawa Y, Mori Y, Uchinuma E, Takato T, Hoshi K (2007) Three-dimensional microenvironments retain chondrocyte phenotypes during proliferation culture. Tissue Eng 13(7):1583–1592CrossRefPubMedGoogle Scholar
  88. 88.
    Hasegawa A, Yonezawa T, Taniguchi N, Otabe K, Akasaki Y, Matsukawa T, Saito M, Neo M, Marmorstein LY, Lotz MK (2016) Fibulin-3 in joint aging and osteoarthritis pathogenesis. Arthritis Rheumatol 69(3):576–585CrossRefGoogle Scholar
  89. 89.
    Jones SW, Brockbank SM, Mobbs ML, Le Good NJ, Soma-Haddrick S, Heuze AJ, Langham CJ, Timms D, Newham P, Needham MR (2006) The orphan G-protein coupled receptor RDC1: evidence for a role in chondrocyte hypertrophy and articular cartilage matrix turnover. Osteoarthritis Cartilage 14(6):597–608CrossRefPubMedGoogle Scholar
  90. 90.
    Le LT, Swingler TE, Clark IM (2013) Review: the role of microRNAs in osteoarthritis and chondrogenesis. Arthritis Rheum 65(8):1963–1974CrossRefPubMedGoogle Scholar
  91. 91.
    Martinez-Sanchez A, Dudek KA, Murphy CL (2012) Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). J Biol Chem 287(2):916–924CrossRefPubMedGoogle Scholar
  92. 92.
    Diederichs S, Gabler J, Autenrieth J, Kynast KL, Merle C, Walles H, Utikal J, Richter W (2016) Differential regulation of SOX9 protein during chondrogenesis of induced pluripotent stem cells versus mesenchymal stromal cells: a shortcoming for cartilage formation. Stem Cells Dev 25(8):598–609CrossRefPubMedGoogle Scholar
  93. 93.
    Ukai T, Sato M, Akutsu H, Umezawa A, Mochida J (2012) MicroRNA-199a-3p, microRNA-193b, and microRNA-320c are correlated to aging and regulate human cartilage metabolism. J Orthop Res 30(12):1915–1922CrossRefPubMedGoogle Scholar
  94. 94.
    Lee S, Yoon DS, Paik S, Lee KM, Jang Y, Lee JW (2014) microRNA-495 inhibits chondrogenic differentiation in human mesenchymal stem cells by targeting Sox9. Stem Cells Dev 23(15):1798–1808CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Martinez-Sanchez A, Murphy CL (2013) miR-1247 functions by targeting cartilage transcription factor SOX9. J Biol Chem 288(43):30802–30814CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Xu J, Kang Y, Liao WM, Yu L (2012) MiR-194 regulates chondrogenic differentiation of human adipose-derived stem cells by targeting Sox5. PLoS ONE 7(3):e31861CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Song J, Kim D, Chun CH, Jin EJ (2013) MicroRNA-375, a new regulator of cadherin-7, suppresses the migration of chondrogenic progenitors. Cell Signal 25(3):698–706CrossRefPubMedGoogle Scholar
  98. 98.
    Kim D, Song J, Kim S, Park HM, Chun CH, Sonn J, Jin EJ (2012) MicroRNA-34a modulates cytoskeletal dynamics through regulating RhoA/Rac1 cross-talk in chondroblasts. J Biol Chem 287(15):12501–12509CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Kim D, Song J, Kim S, Kang SS, Jin EJ (2011) MicroRNA-142-3p regulates TGF-beta3-mediated region-dependent chondrogenesis by regulating ADAM9. Biochem Biophys Res Commun 414(4):653–659CrossRefPubMedGoogle Scholar
  100. 100.
    Kim D, Song J, Kim S, Chun CH, Jin EJ (2011) MicroRNA-34a regulates migration of chondroblast and IL-1beta-induced degeneration of chondrocytes by targeting EphA5. Biochem Biophys Res Commun 415(4):551–557CrossRefPubMedGoogle Scholar
  101. 101.
    Zhou X, Wang J, Sun H, Qi Y, Xu W, Luo D, Jin X, Li C, Chen W, Lin Z, Li F, Zhang R, Li G (2016) MicroRNA-99a regulates early chondrogenic differentiation of rat mesenchymal stem cells by targeting the BMPR2 gene. Cell Tissue Res 366(1):143–153CrossRefPubMedGoogle Scholar
  102. 102.
    Yoshizuka M, Nakasa T, Kawanishi Y, Hachisuka S, Furuta T, Miyaki S, Adachi N, Ochi M (2016) Inhibition of microRNA-222 expression accelerates bone healing with enhancement of osteogenesis, chondrogenesis, and angiogenesis in a rat refractory fracture model. J Orthop Sci 21(6):852–858CrossRefPubMedGoogle Scholar
  103. 103.
    Guerit D, Brondello JM, Chuchana P, Philipot D, Toupet K, Bony C, Jorgensen C, Noel D (2014) FOXO3A regulation by miRNA-29a Controls chondrogenic differentiation of mesenchymal stem cells and cartilage formation. Stem Cells Dev 23(11):1195–1205CrossRefPubMedGoogle Scholar
  104. 104.
    Seidl CI, Martinez-Sanchez A, Murphy CL (2016) Derepression of MicroRNA-138 contributes to loss of the human articular chondrocyte phenotype. Arthritis Rheumatol 68(2):398–409CrossRefPubMedGoogle Scholar
  105. 105.
    Song J, Lee M, Kim D, Han J, Chun CH, Jin EJ (2013) MicroRNA-181b regulates articular chondrocytes differentiation and cartilage integrity. Biochem Biophys Res Commun 431(2):210–214CrossRefPubMedGoogle Scholar
  106. 106.
    Paik S, Jung HS, Lee S, Yoon DS, Park MS, Lee JW (2012) miR-449a regulates the chondrogenesis of human mesenchymal stem cells through direct targeting of lymphoid enhancer-binding factor-1. Stem Cells Dev 21(18):3298–3308CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Chen WK, Yu XH, Yang W, Wang C, He WS, Yan YG, Zhang J, Wang WJ (2017) lncRNAs: novel players in intervertebral disc degeneration and osteoarthritis. Cell Prolif 50(1):e12313CrossRefGoogle Scholar
  108. 108.
    Liu Q, Zhang X, Hu X, Dai L, Fu X, Zhang J, Ao Y (2016) Circular RNA related to the chondrocyte ECM regulates MMP13 expression by functioning as a MiR-136 ‘Sponge’ in human cartilage degradation. Sci Rep 6:22572CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Liu Q, Zhang X, Dai L, Hu X, Zhu J, Li L, Zhou C, Ao Y (2014) Long noncoding RNA related to cartilage injury promotes chondrocyte extracellular matrix degradation in osteoarthritis. Arthritis Rheumatol 66(4):969–978CrossRefPubMedGoogle Scholar
  110. 110.
    Li J, Dong S (2016) The signaling pathways involved in chondrocyte differentiation and hypertrophic differentiation. Stem Cells Int 2016:2470351PubMedPubMedCentralGoogle Scholar
  111. 111.
    de Vries-van Melle ML, Narcisi R, Kops N, Koevoet WJ, Bos PK, Murphy JM, Verhaar JA, van der Kraan PM, van Osch GJ (2014) Chondrogenesis of mesenchymal stem cells in an osteochondral environment is mediated by the subchondral bone. Tissue Eng Part A 20(1–2):23–33CrossRefPubMedGoogle Scholar
  112. 112.
    Fahy N, de Vries-van Melle ML, Lehmann J, Wei W, Grotenhuis N, Farrell E, van der Kraan PM, Murphy JM, Bastiaansen-Jenniskens YM, van Osch GJ (2014) Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state. Osteoarthritis Cartilage 22(8):1167–1175CrossRefPubMedGoogle Scholar
  113. 113.
    Wei W, Rudjito E, Fahy N, Verhaar JA, Clockaerts S, Bastiaansen-Jenniskens YM, van Osch GJ (2015) The infrapatellar fat pad from diseased joints inhibits chondrogenesis of mesenchymal stem cells. Eur Cell Mater 30:303–314CrossRefPubMedGoogle Scholar
  114. 114.
    Lane SW, Williams DA, Watt FM (2014) Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 32(8):795–803CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Shapiro F, Koide S, Glimcher MJ (1993) Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J Bone Joint Surg Am 75(4):532–553CrossRefPubMedGoogle Scholar
  116. 116.
    Hunziker EB, Rosenberg LC (1996) Repair of partial-thickness defects in articular cartilage: cell recruitment from the synovial membrane. J Bone Joint Surg Am 78(5):721–733CrossRefPubMedGoogle Scholar
  117. 117.
    Chan CM, Macdonald CD, Litherland GJ, Wilkinson DJ, Skelton A, Europe-Finner GN, Rowan AD (2017) Cytokine-induced MMP13 expression in human chondrocytes is dependent on activating transcription factor 3 (ATF3) regulation. J Biol Chem 292(5):1625–1636CrossRefPubMedGoogle Scholar
  118. 118.
    Lu X, Lin J, Jin J, Qian W, Weng X (2016) Hsa-miR-15a exerts protective effects against osteoarthritis by targeting aggrecanase-2 (ADAMTS5) in human chondrocytes. Int J Mol Med 37(2):509–516CrossRefPubMedGoogle Scholar
  119. 119.
    Akagi R, Akatsu Y, Fisch KM, Alvarez-Garcia O, Teramura T, Muramatsu Y, Saito M, Sasho T, Su AI, Lotz MK (2016) Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-beta signaling in chondrocytes. Osteoarthr Cartil. doi: 10.1016/j.joca.2016.11.007 PubMedCentralGoogle Scholar
  120. 120.
    Preitschopf A, Schorghofer D, Kinslechner K, Schutz B, Zwickl H, Rosner M, Joo JG, Nehrer S, Hengstschlager M, Mikula M (2016) Rapamycin-Induced Hypoxia Inducible Factor 2A Is Essential for Chondrogenic Differentiation of Amniotic Fluid Stem Cells. Stem Cells Transl Med 5(5):580–590CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Andre EM, Pensado A, Resnier P, Braz L, Rosa da Costa AM, Passirani C, Sanchez A, Montero-Menei CN (2016) Characterization and comparison of two novel nanosystems associated with siRNA for cellular therapy. Int J Pharm 497(1–2):255–267CrossRefPubMedGoogle Scholar
  122. 122.
    Zhao J, Fan X, Zhang Q, Sun F, Li X, Xiong C, Zhang C, Fan H (2014) Chitosan-plasmid DNA nanoparticles encoding small hairpin RNA targeting MMP-3 and -13 to inhibit the expression of dedifferentiation related genes in expanded chondrocytes. J Biomed Mater Res A 102(2):373–380CrossRefPubMedGoogle Scholar
  123. 123.
    Schade A, Delyagina E, Scharfenberg D, Skorska A, Lux C, David R, Steinhoff G (2013) Innovative strategy for microRNA delivery in human mesenchymal stem cells via magnetic nanoparticles. Int J Mol Sci 14(6):10710–10726CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Peng X, Yang L, Chang H, Dai G, Wang F, Duan X, Guo L, Zhang Y, Chen G (2014) Wnt/beta-catenin signaling regulates the proliferation and differentiation of mesenchymal progenitor cells through the p53 pathway. PLoS ONE 9(5):e97283CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Laine SK, Alm JJ, Virtanen SP, Aro HT, Laitala-Leinonen TK (2012) MicroRNAs miR-96, miR-124, and miR-199a regulate gene expression in human bone marrow-derived mesenchymal stem cells. J Cell Biochem 113(8):2687–2695CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Department of Orthopaedics, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands
  2. 2.Department of Biomedical and Specialty Surgical SciencesUniversity of FerraraFerraraItaly
  3. 3.Department of Otorhinolaryngology, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands

Personalised recommendations