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Gene Therapy in Articular Cartilage Repair

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Developing Insights in Cartilage Repair

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Abstract

The restoration of damaged articular cartilage remains one of the biggest challenges in modern clinical orthopaedics. There is no pharmacological treatment that promotes the repair of cartilage, and non-operative treatment inevitably leads to the development of premature osteoarthritis. Current treatment modalities include microfracture, transplantation of osteochondral grafts and autologous chondrocyte implantation (ACI), each having its own benefits and shortcomings. New biological approaches to cartilage repair that are based on the use of cells and molecules that promote chondrogenesis and/or inhibit cartilage breakdown offer a promising alternative to current treatment options. Chondrogenesis is a precisely orchestrated process which involves many growth factors and signaling molecules, and by modifying the local cellular environment, it is possible to enhance formation of more natural cartilage tissue within the defect. These bioactive molecules are difficult to administer effectively. For those that are proteins or RNA molecules, gene transfer has emerged as an attractive option for their sustained synthesis at the site of repair. To accomplish this task, two main strategies have been explored. The direct or in vivo approach delivers exogenous DNA directly into the joint. In this case synovial lining cells are the main site of gene transfer; depending on the vector, cells around or within the defect may also be genetically modified. During indirect or ex vivo delivery, cells are recovered, genetically manipulated outside the body, and then returned to the defect. Delivery of the genetic material to the living cell can be accomplished by use of either viral or non-viral vectors. While viral vectors are much more effective, they raise several safety concerns. Numerous preclinical animal studies have confirmed the effectiveness of these approaches in joints, and several phase I and II clinical gene therapy studies in the local treatment of arthritis provide reason for cautious optimism. This chapter will provide insight into the field of gene therapy in cartilage repair, and its potential for safe and effective clinical translation.

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References

  1. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80.

    PubMed  CAS  Google Scholar 

  2. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65.

    PubMed  CAS  Google Scholar 

  3. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318–22.

    PubMed  CAS  Google Scholar 

  4. Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643–50.

    PubMed  CAS  Google Scholar 

  5. Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008;28(12):2303–4.

    PubMed  CAS  Google Scholar 

  6. Carpentier AC, Frisch F, Labbe SM, Gagnon R, de Wal J, Greentree S, et al. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012;97(5):1635–44.

    PubMed  CAS  Google Scholar 

  7. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology. 2002;3(5):257–64.

    PubMed  CAS  Google Scholar 

  8. Martin JA, Buckwalter JA. Human chondrocyte senescence and osteoarthritis. Biorheology. 2002;39(1–2):145–52.

    PubMed  CAS  Google Scholar 

  9. Martin JA, Buckwalter JA. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am. 2003;85-A Suppl 2:106–10.

    PubMed  Google Scholar 

  10. Skaalure SC, Milligan IL, Bryant SJ. Age impacts extracellular matrix metabolism in chondrocytes encapsulated in degradable hydrogels. Biomed Mater. 2012;7(2):024111.

    PubMed  Google Scholar 

  11. Bader DL, Salter DM, Chowdhury TT. Biomechanical influence of cartilage homeostasis in health and disease. Arthritis. 2011;2011:979032.

    PubMed  CAS  Google Scholar 

  12. Evans CH, Georgescu HI. Observations on the senescence of cells derived from articular cartilage. Mech Ageing Dev. 1983;22(2):179–91.

    PubMed  CAS  Google Scholar 

  13. Gomoll AH, Farr J, Gillogly SD, Kercher JS, Minas T. Surgical management of articular cartilage defects of the knee. Instr Course Lect. 2011;60:461–83.

    PubMed  Google Scholar 

  14. Conwell CC, Huang L. Recent advances in non-viral gene delivery. Adv Genet. 2005;53:3–18.

    PubMed  CAS  Google Scholar 

  15. Oligino TJ, Yao Q, Ghivizzani SC, Robbins P. Vector systems for gene transfer to joints. Clin Orthop Relat Res. 2000;379(Suppl):S17–30.

    PubMed  Google Scholar 

  16. Madry H, Kaul G, Cucchiarini M, Stein U, Zurakowski D, Remberger K, et al. Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther. 2005;12(15):1171–9.

    PubMed  CAS  Google Scholar 

  17. Kaul G, Cucchiarini M, Arntzen D, Zurakowski D, Menger MD, Kohn D, et al. Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo. J Gene Med. 2006;8(1):100–11.

    PubMed  CAS  Google Scholar 

  18. Katayama R, Wakitani S, Tsumaki N, Morita Y, Matsushita I, Gejo R, et al. Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow. Rheumatology (Oxford). 2004;43(8):980–5.

    CAS  Google Scholar 

  19. Kim HJ, Im GI. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells. Stem Cells Dev. 2011;20(12):2103–14.

    PubMed  CAS  Google Scholar 

  20. Cucchiarini M, Madry H. Gene therapy for cartilage defects. J Gene Med. 2005;7(12):1495–509.

    PubMed  CAS  Google Scholar 

  21. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348(3):255–6.

    PubMed  Google Scholar 

  22. Gouze E, Pawliuk R, Gouze JN, Pilapil C, Fleet C, Palmer GD, et al. Lentiviral-mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation. Mol Ther. 2003;7(4):460–6.

    PubMed  CAS  Google Scholar 

  23. Gouze E, Pawliuk R, Pilapil C, Gouze JN, Fleet C, Palmer GD, et al. In vivo gene delivery to synovium by lentiviral vectors. Mol Ther. 2002;5(4):397–404.

    PubMed  CAS  Google Scholar 

  24. Xiao X, Li J, Samulski RJ. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol. 1996;70(11):8098–108.

    PubMed  CAS  Google Scholar 

  25. Grieger JC, Choi VW, Samulski RJ. Production and characterization of adeno-associated viral vectors. Nat Protoc. 2006;1(3):1412–28.

    PubMed  CAS  Google Scholar 

  26. Toh ML, Hong SS, van de Loo F, Franqueville L, Lindholm L, van den Berg W, et al. Enhancement of adenovirus-mediated gene delivery to rheumatoid arthritis synoviocytes and synovium by fiber modifications: role of arginine-glycine-aspartic acid (RGD)- and non-RGD-binding integrins. J Immunol. 2005;175(11):7687–98.

    PubMed  CAS  Google Scholar 

  27. Kay JD, Gouze E, Oligino TJ, Gouze JN, Watson RS, Levings PP, et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus. J Gene Med. 2009;11(7):605–14.

    PubMed  CAS  Google Scholar 

  28. Shi S, Mercer S, Trippel SB. Effect of transfection strategy on growth factor overexpression by articular chondrocytes. J Orthop Res. 2010;28(1):103–9.

    PubMed  CAS  Google Scholar 

  29. Marijanovic I, Radnic M, Matic I, Erceg-Ivkosic I. Osteogenesis imperfecta and achievements in cell and gene therapy. Acta Med Croatica. 2010;64(3):191–200.

    PubMed  CAS  Google Scholar 

  30. Mohr L, Geissler M, Blum HE. Gene therapy for malignant liver disease. Expert Opin Biol Ther. 2002;2(2):163–75.

    PubMed  CAS  Google Scholar 

  31. Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIlwraith CW. IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects. Clin Orthop Relat Res. 2007;462:221–8.

    PubMed  Google Scholar 

  32. Nixon AJ, Brower-Toland BD, Bent SJ, Saxer RA, Wilke MJ, Robbins PD, et al. Insulinlike growth factor-I gene therapy applications for cartilage repair. Clin Orthop Relat Res. 2000;379(Suppl):201–13.

    Google Scholar 

  33. Nixon AJ, Haupt JL, Frisbie DD, Morisset SS, McIlwraith CW, Robbins PD, et al. Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy. Gene Ther. 2005;12(2):177–86.

    PubMed  CAS  Google Scholar 

  34. Sun Y, Chen X, Xiao D. Tetracycline-inducible expression systems: new strategies and practices in the transgenic mouse modeling. Acta Biochim Biophys Sin (Shanghai). 2007;39(4):235–46.

    CAS  Google Scholar 

  35. Varley AW, Munford RS. Physiologically responsive gene therapy. Mol Med Today. 1998;4(10):445–51.

    PubMed  CAS  Google Scholar 

  36. Wheatley S, Wright E, Jeske Y, MCCormack A, Bowles J, Koopman P. Aetiology of the skeletal dysmorphology syndrome campomelic dysplasia: expression of the Sox9 gene during chondrogenesis in mouse embryos. Ann N Y Acad Sci. 1996;785:350–2.

    PubMed  CAS  Google Scholar 

  37. Lefebvre V, Behringer RR, de Crombrugghe B. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthritis Cartilage. 2001;9(Suppl A):S69–75.

    PubMed  Google Scholar 

  38. Leung VY, Gao B, Leung KK, Melhado IG, Wynn SL, Au TY, et al. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 2011;7(11):e1002356.

    PubMed  CAS  Google Scholar 

  39. Li Y, Tew SR, Russell AM, Gonzalez KR, Hardingham TE, Hawkins RE. Transduction of passaged human articular chondrocytes with adenoviral, retroviral, and lentiviral vectors and the effects of enhanced expression of SOX9. Tissue Eng. 2004;10(3–4):575–84.

    PubMed  CAS  Google Scholar 

  40. Cucchiarini M, Thurn T, Weimer A, Kohn D, Terwilliger EF, Madry H. Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9. Arthritis Rheum. 2007;56(1):158–67.

    PubMed  CAS  Google Scholar 

  41. Tew SR, Li Y, Pothacharoen P, Tweats LM, Hawkins RE, Hardingham TE. Retroviral transduction with SOX9 enhances re-expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes. Osteoarthritis Cartilage. 2005;13(1):80–9.

    PubMed  Google Scholar 

  42. Yang HN, Park JS, Woo DG, Jeon SY, Do HJ, Lim HY, et al. Chondrogenesis of mesenchymal stem cells and dedifferentiated chondrocytes by transfection with SOX Trio genes. Biomaterials. 2011;32(30):7695–704.

    PubMed  CAS  Google Scholar 

  43. Im GI, Kim HJ, Lee JH. Chondrogenesis of adipose stem cells in a porous PLGA scaffold impregnated with plasmid DNA containing SOX trio (SOX-5,-6 and -9) genes. Biomaterials. 2011;32(19):4385–92.

    PubMed  CAS  Google Scholar 

  44. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, et al. The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis Rheum. 2004;50(11):3561–73.

    PubMed  CAS  Google Scholar 

  45. Ivkovic A, Marijanovic I, Hudetz D, Porter RM, Pecina M, Evans CH. Regenerative medicine and tissue engineering in orthopaedic surgery. Front Biosci (Elite Ed). 2011;3:923–44.

    Google Scholar 

  46. Huang YL, Qiu RF, Mai WY, Kuang J, Cai XY, Dong YG, et al. Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro. J Zhejiang Univ Sci B. 2012;13(1):20–8.

    PubMed  CAS  Google Scholar 

  47. Madry H, Zurakowski D, Trippel SB. Overexpression of human insulin-like growth factor-I promotes new tissue formation in an ex vivo model of articular chondrocyte transplantation. Gene Ther. 2001;8(19):1443–9.

    PubMed  CAS  Google Scholar 

  48. Mi Z, Ghivizzani SC, Lechman ER, Jaffurs D, Glorioso JC, Evans CH, et al. Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum. 2000;43(11):2563–70.

    PubMed  CAS  Google Scholar 

  49. Weimer A, Madry H, Venkatesan JK, Schmitt G, Frisch J, Wezel A, et al. Benefits of rAAV-mediated IGF-I overexpression for the long-term reconstruction of human osteoarthritic cartilage by modulation of the IGF-I axis. Mol Med. 2012;18:346–58.

    Google Scholar 

  50. Hidaka C, Quitoriano M, Warren RF, Crystal RG. Enhanced matrix synthesis and in vitro formation of cartilage-like tissue by genetically modified chondrocytes expressing BMP-7. J Orthop Res. 2001;19(5):751–8.

    PubMed  CAS  Google Scholar 

  51. Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res. 2003;21(4):573–83.

    PubMed  CAS  Google Scholar 

  52. Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, et al. Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Arthritis Rheum. 2006;54(2):433–42.

    PubMed  CAS  Google Scholar 

  53. Steinert AF, Proffen B, Kunz M, Hendrich C, Ghivizzani SC, Noth U, et al. Hypertrophy is induced during the in vitro chondrogenic differentiation of human mesenchymal stem cells by bone morphogenetic protein-2 and bone morphogenetic protein-4 gene transfer. Arthritis Res Ther. 2009;11(5):R148.

    PubMed  Google Scholar 

  54. Shuler FD, Georgescu HI, Niyibizi C, Studer RK, Mi Z, Johnstone B, et al. Increased matrix synthesis following adenoviral transfer of a transforming growth factor beta1 gene into articular chondrocytes. J Orthop Res. 2000;18(4):585–92.

    PubMed  CAS  Google Scholar 

  55. Moller HD, Fu FH, Niyibizi C, Studer RK, Georgescu HJ, Robbins PD, et al. TGF-beta-1 gene transfer in joint cartilage cells. Stimulating effect in extracellular matrix synthesis. Orthopade. 2000;29(2):75–9.

    PubMed  CAS  Google Scholar 

  56. Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S, et al. Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther. 2010;17(6):779–89.

    PubMed  CAS  Google Scholar 

  57. Wang W, Li B, Li Y, Jiang Y, Ouyang H, Gao C. In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes. Biomaterials. 2010;31(23):5953–65.

    PubMed  CAS  Google Scholar 

  58. Ha CW, Noh MJ, Choi KB, Lee KH. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy. 2012;14(2):247–56.

    PubMed  CAS  Google Scholar 

  59. Mi Z, Ghivizzani SC, Lechman E, Glorioso JC, Evans CH, Robbins PD. Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. Arthritis Res Ther. 2003;5(3):R132–9.

    PubMed  CAS  Google Scholar 

  60. Watson RS, Gouze E, Levings PP, Bush ML, Kay JD, Jorgensen MS, et al. Gene delivery of TGF-beta1 induces arthrofibrosis and chondrometaplasia of synovium in vivo. Lab Invest. 2010;90(11):1615–27.

    PubMed  CAS  Google Scholar 

  61. van Beuningen HM, van der Kraan PM, Arntz OJ, van den Berg WB. Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest. 1994;71(2):279–90.

    PubMed  Google Scholar 

  62. Vincent TL. Fibroblast growth factor 2: good or bad guy in the joint? Arthritis Res Ther. 2011;13(5):127.

    PubMed  CAS  Google Scholar 

  63. Orth P, Kaul G, Cucchiarini M, Zurakowski D, Menger MD, Kohn D, et al. Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo. Knee Surg Sports Traumatol Arthrosc. 2011;19(12):2119–30.

    PubMed  Google Scholar 

  64. Chang SC, Hoang B, Thomas JT, Vukicevic S, Luyten FP, Ryba NJ, et al. Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. J Biol Chem. 1994;269(45):28227–34.

    PubMed  CAS  Google Scholar 

  65. Luyten FP. Cartilage-derived morphogenetic protein-1. Int J Biochem Cell Biol. 1997;29(11):1241–4.

    PubMed  CAS  Google Scholar 

  66. Storm EE, Kingsley DM. GDF5 coordinates bone and joint formation during digit development. Dev Biol. 1999;209(1):11–27.

    PubMed  CAS  Google Scholar 

  67. Hotten GC, Matsumoto T, Kimura M, Bechtold RF, Kron R, Ohara T, et al. Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs. Growth Factors. 1996;13(1–2):65–74.

    PubMed  CAS  Google Scholar 

  68. Tsumaki N, Tanaka K, Arikawa-Hirasawa E, Nakase T, Kimura T, Thomas JT, et al. Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. J Cell Biol. 1999;144(1):161–73.

    PubMed  CAS  Google Scholar 

  69. Bai X, Xiao Z, Pan Y, Hu J, Pohl J, Wen J, et al. Cartilage-derived morphogenetic protein-1 promotes the differentiation of mesenchymal stem cells into chondrocytes. Biochem Biophys Res Commun. 2004;325(2):453–60.

    PubMed  CAS  Google Scholar 

  70. Feng G, Wan Y, Balian G, Laurencin CT, Li X. Adenovirus-mediated expression of growth and differentiation factor-5 promotes chondrogenesis of adipose stem cells. Growth Factors. 2008;26(3):132–42.

    PubMed  CAS  Google Scholar 

  71. Rickert M, Wang H, Wieloch P, Lorenz H, Steck E, Sabo D, et al. Adenovirus-mediated gene transfer of growth and differentiation factor-5 into tenocytes and the healing rat Achilles tendon. Connect Tissue Res. 2005;46(4–5):175–83.

    PubMed  CAS  Google Scholar 

  72. Liang H, Ma SY, Feng G, Shen FH, Joshua LX. Therapeutic effects of adenovirus-mediated growth and differentiation factor-5 in a mice disc degeneration model induced by annulus needle puncture. Spine J. 2010;10(1):32–41.

    PubMed  Google Scholar 

  73. Evans CH, Robbins PD, Ghivizzani SC, Herndon JH, Kang R, Bahnson AB, et al. Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Hum Gene Ther. 1996;7(10):1261–80.

    PubMed  CAS  Google Scholar 

  74. Evans CH, Robbins PD, Ghivizzani SC, Wasko MC, Tomaino MM, Kang R, et al. Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A. 2005;102(24):8698–703.

    PubMed  CAS  Google Scholar 

  75. Fernandes J, Tardif G, Martel-Pelletier J, Lascau-Coman V, Dupuis M, Moldovan F, et al. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol. 1999;154(4):1159–69.

    PubMed  CAS  Google Scholar 

  76. Roessler BJ, Hartman JW, Vallance DK, Latta JM, Janich SL, Davidson BL. Inhibition of interleukin-1-induced effects in synoviocytes transduced with the human IL-1 receptor antagonist cDNA using an adenoviral vector. Hum Gene Ther. 1995;6(3):307–16.

    PubMed  CAS  Google Scholar 

  77. Zhang HG, Xie J, Yang P, Wang Y, Xu L, Liu D, et al. Adeno-associated virus production of soluble tumor necrosis factor receptor neutralizes tumor necrosis factor alpha and reduces arthritis. Hum Gene Ther. 2000;11(17):2431–42.

    PubMed  CAS  Google Scholar 

  78. Gould D, Yousaf N, Fatah R, Subang MC, Chernajovsky Y. Gene therapy with an improved doxycycline-regulated plasmid encoding a tumour necrosis factor-alpha inhibitor in experimental arthritis. Arthritis Res Ther. 2007;9(1):R7.

    PubMed  Google Scholar 

  79. Adriaansen J, Khoury M, de Cortie CJ, Fallaux FJ, Bigey P, Scherman D, et al. Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent. Ann Rheum Dis. 2007;66(9):1143–50.

    PubMed  CAS  Google Scholar 

  80. Kafienah W, Al-Fayez F, Hollander AP, Barker MD. Inhibition of cartilage degradation: a combined tissue engineering and gene therapy approach. Arthritis Rheum. 2003;48(3):709–18.

    PubMed  CAS  Google Scholar 

  81. Bondeson J, Lauder S, Wainwright S, Amos N, Evans A, Hughes C, et al. Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent. J Rheumatol. 2007;34(3):523–33.

    PubMed  CAS  Google Scholar 

  82. Surendran S, Kim SH, Jee BK, Ahn SH, Gopinathan P, Han CW. Anti-apoptotic Bcl-2 gene transfection of human articular chondrocytes protects against nitric oxide-induced apoptosis. J Bone Joint Surg Br. 2006;88(12):1660–5.

    PubMed  CAS  Google Scholar 

  83. Grossin L, Cournil-Henrionnet C, Pinzano A, Gaborit N, Dumas D, Etienne S, et al. Gene transfer with HSP 70 in rat chondrocytes confers cytoprotection in vitro and during experimental osteoarthritis. FASEB J. 2006;20(1):65–75.

    PubMed  CAS  Google Scholar 

  84. Piera-Velazquez S, Jimenez SA, Stokes D. Increased life span of human osteoarthritic chondrocytes by exogenous expression of telomerase. Arthritis Rheum. 2002;46(3):683–93.

    PubMed  CAS  Google Scholar 

  85. Sato M, Shin-Ya K, Lee JI, Ishihara M, Nagai T, Kaneshiro N, et al. Human telomerase reverse transcriptase and glucose-regulated protein 78 increase the life span of articular chondrocytes and their repair potential. BMC Musculoskelet Disord. 2012;13(1):51.

    PubMed  CAS  Google Scholar 

  86. Nonomura Y, Kohsaka H, Nagasaka K, Miyasaka N. Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis. J Immunol. 2003;171(9):4913–9.

    PubMed  CAS  Google Scholar 

  87. Shi S, Mercer S, Eckert GJ, Trippel SB. Regulation of articular chondrocyte aggrecan and collagen gene expression by multiple growth factor gene transfer. J Orthop Res. 2012;30:1026–31.

    PubMed  CAS  Google Scholar 

  88. Chen B, Qin J, Wang H, Magdalou J, Chen L. Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp Mol Med. 2010;42(10):684–95.

    PubMed  CAS  Google Scholar 

  89. Madry H, Orth P, Kaul G, Zurakowski D, Menger MD, Kohn D, et al. Acceleration of articular cartilage repair by combined gene transfer of human insulin-like growth factor I and fibroblast growth factor-2 in vivo. Arch Orthop Trauma Surg. 2010;130(10):1311–22.

    PubMed  Google Scholar 

  90. Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5.

    PubMed  CAS  Google Scholar 

  91. Dong S, Yang B, Guo H, Kang F. MicroRNAs regulate osteogenesis and chondrogenesis. Biochem Biophys Res Commun. 2012;418(4):587–91.

    PubMed  CAS  Google Scholar 

  92. Miyaki S, Nakasa T, Otsuki S, Grogan SP, Higashiyama R, Inoue A, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009;60(9):2723–30.

    PubMed  CAS  Google Scholar 

  93. Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S, et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 2010;24(11):1173–85.

    PubMed  CAS  Google Scholar 

  94. Araldi E, Schipani E. MicroRNA-140 and the silencing of osteoarthritis. Genes Dev. 2010;24(11):1075–80.

    PubMed  CAS  Google Scholar 

  95. Tardif G, Hum D, Pelletier JP, Duval N, Martel-Pelletier J. Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes. BMC Musculoskelet Disord. 2009;10:148.

    PubMed  Google Scholar 

  96. Yang B, Guo H, Zhang Y, Dong S, Ying D. The microRNA expression profiles of mouse mesenchymal stem cell during chondrogenic differentiation. BMB Rep. 2011;44(1):28–33.

    PubMed  CAS  Google Scholar 

  97. Yang B, Guo H, Zhang Y, Chen L, Ying D, Dong S. MicroRNA-145 regulates chondrogenic differentiation of mesenchymal stem cells by targeting Sox9. PLoS One. 2011;6(7):e21679.

    PubMed  CAS  Google Scholar 

  98. Martinez-Sanchez A, Dudek KA, Murphy CL. Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). J Biol Chem. 2012;287(2):916–24.

    PubMed  CAS  Google Scholar 

  99. Yamasaki K, Nakasa T, Miyaki S, Ishikawa M, Deie M, Adachi N, et al. Expression of microRNA-146a in osteoarthritis cartilage. Arthritis Rheum. 2009;60(4):1035–41.

    PubMed  CAS  Google Scholar 

  100. Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M. The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum. 2011;63(6):1582–90.

    PubMed  CAS  Google Scholar 

  101. Jones SW, Watkins G, Le Good N, Roberts S, Murphy CL, Brockbank SM, et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13. Osteoarthritis Cartilage. 2009;17(4):464–72.

    PubMed  CAS  Google Scholar 

  102. Abouheif MM, Nakasa T, Shibuya H, Niimoto T, Kongcharoensombat W, Ochi M. Silencing microRNA-34a inhibits chondrocyte apoptosis in a rat osteoarthritis model in vitro. Rheumatology (Oxford). 2010;49(11):2054–60.

    CAS  Google Scholar 

  103. Wehling P, Reinecke J, Baltzer AW, Granrath M, Schulitz KP, Schultz C, et al. Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum Gene Ther. 2009;20(2):97–101.

    PubMed  CAS  Google Scholar 

  104. Kafienah W, Jakob M, Demarteau O, Frazer A, Barker MD, Martin I, et al. Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng. 2002;8(5):817–26.

    PubMed  CAS  Google Scholar 

  105. Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, et al. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther. 2005;12(2):229–38.

    PubMed  CAS  Google Scholar 

  106. Seo S, Na K. Mesenchymal stem cell-based tissue engineering for chondrogenesis. J Biomed Biotechnol. 2011;2011:806891.

    PubMed  Google Scholar 

  107. Park J, Gelse K, Frank S, von der Mark K, Aigner T, Schneider H. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. J Gene Med. 2006;8(1):112–25.

    PubMed  CAS  Google Scholar 

  108. Gelse K, von der Mark K, Aigner T, Park J, Schneider H. Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum. 2003;48(2):430–41.

    PubMed  CAS  Google Scholar 

  109. Pascher A, Palmer GD, Steinert A, Oligino T, Gouze E, Gouze JN, et al. Gene delivery to cartilage defects using coagulated bone marrow aspirate. Gene Ther. 2004;11(2):133–41.

    PubMed  CAS  Google Scholar 

  110. Pelttari K, Steck E, Richter W. The use of mesenchymal stem cells for chondrogenesis. Injury. 2008;39 Suppl 1:S58–65.

    PubMed  Google Scholar 

  111. Wei Y, Zeng W, Wan R, Wang J, Zhou Q, Qiu S, et al. Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. Eur Cell Mater. 2012;23:1–12.

    PubMed  CAS  Google Scholar 

  112. Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy–lost in translation? J Cell Physiol. 2012;227(2):416–20.

    PubMed  CAS  Google Scholar 

  113. Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy’s first death. Arthritis Res Ther. 2008;10(3):110.

    PubMed  Google Scholar 

  114. Bakker AC, Joosten LA, Arntz OJ, Helsen MM, Bendele AM, van de Loo FA, et al. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum. 1997;40(5):893–900.

    PubMed  CAS  Google Scholar 

  115. Gelse K, Jiang QJ, Aigner T, Ritter T, Wagner K, Poschl E, et al. Fibroblast-mediated delivery of growth factor complementary DNA into mouse joints induces chondrogenesis but avoids the disadvantages of direct viral gene transfer. Arthritis Rheum. 2001;44(8):1943–53.

    PubMed  CAS  Google Scholar 

  116. Kon E, Delcogliano M, Filardo G, Busacca M, Di Martino A, Marcacci M. Novel nano-composite multilayered biomaterial for osteochondral regeneration: a pilot clinical trial. Am J Sports Med. 2011;39(6):1180–90.

    PubMed  Google Scholar 

  117. Ebert JR, Fallon M, Ackland TR, Wood DJ, Janes GC. Arthroscopic matrix-induced autologous chondrocyte implantation: 2-year outcomes. Arthroscopy. 2012;28:952–64.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, St. Catherine’s Hospital, Bracak 8, Zabok, 49240, Croatia

    Alan Ivkovic & Damir Hudetz

  2. Department of Orthopaedic Surgery, University Hospital Sveti Duh, Zagreb, Croatia

    Alan Ivkovic & Damir Hudetz

  3. Department of Biotechnology, University of Rijeka, Rijeka, Croatia

    Alan Ivkovic & Damir Hudetz

  4. Department of Histology and Embryology, School of Medicine, University of Zagreb, Zagreb, Croatia

    Andreja Vukasovic

  5. Department of Orthopaedic Surgery, Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Ryan M. Porter & Christopher H. Evans

  6. Department of Orthopaedic Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia

    Marko Pecina

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  1. Alan Ivkovic
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  2. Andreja Vukasovic
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  3. Ryan M. Porter
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  4. Damir Hudetz
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  5. Marko Pecina
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  6. Christopher H. Evans
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Correspondence to Alan Ivkovic .

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Editors and Affiliations

  1. Department of Orthopaedic Surgery, Maastricht University Medical Center, Maastricht, The Netherlands

    Pieter J. Emans

  2. Department of Orthopedics, University of Gothenburg, Gothenburg, Sweden

    Lars Peterson

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Ivkovic, A., Vukasovic, A., Porter, R.M., Hudetz, D., Pecina, M., Evans, C.H. (2014). Gene Therapy in Articular Cartilage Repair. In: Emans, P., Peterson, L. (eds) Developing Insights in Cartilage Repair. Springer, London. https://doi.org/10.1007/978-1-4471-5385-6_2

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  • DOI: https://doi.org/10.1007/978-1-4471-5385-6_2

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