Skip to main content

Advertisement

SpringerLink
Log in

Acceleration of articular cartilage repair by combined gene transfer of human insulin-like growth factor I and fibroblast growth factor-2 in vivo

  • Basic Science
  • Published:
Archives of Orthopaedic and Trauma Surgery Aims and scope Submit manuscript

Abstract

Introduction

Improving the biochemical and structural qualities of the new tissue that fills deep osteochondral defects is critical to enhance articular cartilage repair. We developed a novel molecular therapy to increase articular cartilage repair based on a combined strategy to stimulate chondrogenesis by co-transfection of the human insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) in a xenogenic transplantation model.

Materials and methods

NIH 3T3 cells were transfected with expression plasmid vectors containing a cDNA for the E. coli lacZ gene (lacZ implants), the human IGF-I gene (IGF-I implants) or both the human IGF-I and FGF-2 genes (IGF-I/FGF-2 implants). The expression patterns of the transgenes were monitored in vitro for 21 days. LacZ, IGF-I and IGF-I/FGF-2 implants were transplanted into osteochondral defects in the trochlear groove of rabbits. At 3 weeks, the quality of articular cartilage repair was evaluated qualitatively and quantitatively.

Results

Both IGF-I and IGF-I/FGF-2 implants secreted increased levels of the corresponding recombinant proteins in vitro. In vivo, transplantation of the co-transfected IGF-I/FGF-2 implants increased the DNA content of the repair tissue, accelerated the formation of the subchondral bone and improved articular cartilage repair in a magnitude that was larger than with IGF-I alone or when compared to lacZ implants.

Conclusion

These results suggest that gene delivery of a combination of IGF-I and FGF-2 to cartilage defects may be more beneficial than application of IGF-I alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Buckwalter JA, Mankin HJ (1998) Articular cartilage repair and transplantation. Arthritis Rheum 41:1331–1342

    Article  CAS  PubMed  Google Scholar 

  2. Braun S, Vogt S, Imhoff AB (2007) Stadiengerechte operative Knorpeltherapie. Orthopade 36:589–600

    Article  CAS  PubMed  Google Scholar 

  3. O’Driscoll SW, Salter RB (1984) The induction of neochondrogenesis in free intra-articular periosteal autografts under the influence of continuous passive motion. An experimental investigation in the rabbit. J Bone Joint Surg [Am] 66:1248–1257

    Google Scholar 

  4. Rose T, Craatz S, Hepp P et al (2005) The autologous osteochondral transplantation of the knee: clinical results, radiographic findings and histological aspects. Arch Orthop Trauma Surg 125:628–637

    Article  PubMed  Google Scholar 

  5. Steadman JR, Rodkey WG, Rodrigo JJ (2001) Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop 391:S362–S369

    Article  PubMed  Google Scholar 

  6. Johnson LL (1986) Arthroscopic abrasion arthroplasty historical and pathologic perspective: present status. Arthroscopy 2:54–69

    Article  CAS  PubMed  Google Scholar 

  7. Pridie KH (1959) A method of resurfacing osteoarthritic knee joints. Proceedings of the British Orthopaedic Association. J Bone Joint Surg (Br) 41:618

    Google Scholar 

  8. Insall JN (1967) Intra-articular surgery for degenerative arthritis of the knee. A report of the work of the late KH. Pridie. J Bone Joint Surg [Br] 49B:211–228

    Google Scholar 

  9. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895

    Article  CAS  PubMed  Google Scholar 

  10. Bartlett W, Skinner JA, Gooding CR et al (2005) Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Surg Br 87:640–645

    Article  CAS  PubMed  Google Scholar 

  11. Mankin HJ, Buckwalter JA (1996) Restoration of the osteoarthrotic joint. J Bone Joint Surg Am 78:1–2

    CAS  PubMed  Google Scholar 

  12. Martinek V, Ueblacker P, Imhoff AB (2003) Current concepts of gene therapy and cartilage repair. J Bone Joint Surg Br 85:782–788

    CAS  PubMed  Google Scholar 

  13. Cucchiarini M, Madry H (2005) Gene therapy for cartilage defects. J Gene Med 7:1495–1509

    Article  CAS  PubMed  Google Scholar 

  14. Goldring MB, Tsuchimochi K, Ijiri K (2006) The control of chondrogenesis. J Cell Biochem 97:33–44

    Article  CAS  PubMed  Google Scholar 

  15. Knutsen G, Drogset JO, Engebretsen L et al (2007) A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am 89:2105–2112

    Article  PubMed  Google Scholar 

  16. Schofield JN, Wolpert L (1990) Effect of TGF-beta 1, TGF-beta 2, and bFGF on chick cartilage and muscle cell differentiation. Exp Cell Res 191:144–148

    Article  CAS  PubMed  Google Scholar 

  17. Kato Y (1992) Roles of fibroblast growth factor and transforming growth factor-β families in cartilage formation. In: Adolphe M (ed) Biological regulation of the chondrocytes, vol 1. CRC Press, Boca Raton, pp 141–60

  18. Fujimoto E, Ochi M, Kato Y, Mochizuki Y, Sumen Y, Ikuta Y (1999) Beneficial effect of basic fibroblast growth factor on the repair of full-thickness defects in rabbit articular cartilage. Arch Orthop Trauma Surg 119:139–145

    Article  CAS  PubMed  Google Scholar 

  19. Sah RL, Chen AC, Grodzinsky AJ, Trippel SB (1994) Differential effects of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. Arch Biochem Biophys 308:137–147

    Article  CAS  PubMed  Google Scholar 

  20. Trippel SB (1995) Growth factor actions on articular cartilage. J Rheumatol Suppl 43:129–132

    CAS  PubMed  Google Scholar 

  21. Trippel SB, Corvol MT, Dumontier MF, Rappaport R, Hung HH, Mankin HJ (1989) Effect of somatomedin-C/insulin-like growth factor I and growth hormone on cultured growth plate and articular chondrocytes. Pediatr Res 25:76–82

    Article  CAS  PubMed  Google Scholar 

  22. Gelse K, von der Mark K, Aigner T, Park J, Schneider H (2003) Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum 48:430–441

    Article  CAS  PubMed  Google Scholar 

  23. Madry H, Kaul G, Cucchiarini M et al (2005) Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther 12:1171–1179

    Article  CAS  PubMed  Google Scholar 

  24. Kaul G, Cucchiarini M, Arntzen D et al (2006) Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo. J Gene Med 8:100–111

    Article  CAS  PubMed  Google Scholar 

  25. Madry H, Cucchiarini M, Stein U et al (2003) Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid-mediated gene transfer in a gel suspension delivery system. J Gene Med 5:502–509

    Article  CAS  PubMed  Google Scholar 

  26. Kim YJ, Sah RL, Doong JY, Grodzinsky AJ (1988) Fluorometric assay of DNA in cartilage explants using Hoechst 33258. Anal Biochem 174:168–176

    Article  CAS  PubMed  Google Scholar 

  27. Kiernan JA (1999) Histological and histochemical methods—theory and practice, 3rd edn. Butterworth–Heinemann, Oxford

    Google Scholar 

  28. Sellers RS, Peluso D, Morris EA (1997) The effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of articular cartilage. J Bone Joint Surg Am 79:1452–1463

    CAS  PubMed  Google Scholar 

  29. Sellers RS, Zhang R, Glasson SS et al (2000) Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). J Bone Joint Surg Am 82:151–160

    Article  CAS  PubMed  Google Scholar 

  30. Orth P, Weimer A, Kaul G, Kohn D, Cucchiarini M, Madry H (2008) Analysis of novel nonviral gene transfer systems for gene delivery to cells of the musculoskeletal system. Mol Biotechnol 38:137–144

    Article  CAS  PubMed  Google Scholar 

  31. Hunziker EB, Rosenberg LC (1996) Repair of partial-thickness defects in articular cartilage: cell recruitment from the synovial membrane. J Bone Joint Surg Am 78:721–733

    CAS  PubMed  Google Scholar 

  32. Nixon AJ, Fortier LA, Williams J, Mohammed H (1999) Enhanced repair of extensive articular defects by insulin-like growth factor-I-laden fibrin composites. J Orthop Res 17:475–487

    Article  CAS  PubMed  Google Scholar 

  33. Fortier LA, Balkman CE, Sandell LJ, Ratcliffe A, Nixon AJ (2001) Insulin-like growth factor-I gene expression patterns during spontaneous repair of acute articular cartilage injury. J Orthop Res 19:720–728

    Article  CAS  PubMed  Google Scholar 

  34. Fortier LA, Mohammed HO, Lust G, Nixon AJ (2002) Insulin-like growth factor-I enhances cell-based repair of articular cartilage. J Bone Joint Surg Br 84:276–288

    Article  CAS  PubMed  Google Scholar 

  35. Tanaka H, Mizokami H, Shiigi E et al (2004) Effects of basic fibroblast growth factor on the repair of large osteochondral defects of articular cartilage in rabbits: dose–response effects and long-term outcomes. Tissue Eng 10:633–641

    Article  CAS  PubMed  Google Scholar 

  36. Cucchiarini M, Madry H, Ma C et al (2005) Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther 12:229–238

    Article  CAS  PubMed  Google Scholar 

  37. Loeser RF, Chubinskaya S, Pacione C, Im HJ (2005) Basic fibroblast growth factor inhibits the anabolic activity of insulin-like growth factor 1 and osteogenic protein 1 in adult human articular chondrocytes. Arthritis Rheum 52:3910–3917

    Article  CAS  PubMed  Google Scholar 

  38. Bentley G, Greer RB 3rd (1971) Homotransplantation of isolated epiphyseal and articular cartilage chondrocytes into joint surfaces of rabbits. Nature 230:385–388

    Article  CAS  PubMed  Google Scholar 

  39. Paek HJ, Campaner AB, Kim JL et al (2006) Microencapsulated cells genetically modified to overexpress human transforming growth factor-beta1: viability and functionality in allogeneic and xenogeneic implant models. Tissue Eng 12:1733–1739

    Article  CAS  PubMed  Google Scholar 

  40. Reape TJ, Kanczler JM, Ward JP, Thomas CR (1996) IGF-I increases bFGF-induced mitogenesis and upregulates FGFR-1 in rabbit vascular smooth muscle cells. Am J Physiol 270:H1141–H1148

    CAS  PubMed  Google Scholar 

  41. Zheng JL, Helbig C, Gao WQ (1997) Induction of cell proliferation by fibroblast and insulin-like growth factors in pure rat inner ear epithelial cell cultures. J Neurosci 17:216–226

    CAS  PubMed  Google Scholar 

  42. Edmondson SR, Russo VC, McFarlane AC, Wraight CJ, Werther GA (1999) Interactions between growth hormone, insulin-like growth factor I, and basic fibroblast growth factor in melanocyte growth. J Clin Endocrinol Metab 84:1638–1644

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank E. Kabiljagic for the expert technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (DFG MA 2363/1-2 to HM). All performed experiments complied with the current laws of Germany.

Author information

Authors and Affiliations

  1. Institute for Experimental Orthopaedics and Department of Orthopaedic Surgery, Saarland University Medical Center, 66421, Homburg, Germany

    Henning Madry, Patrick Orth, Gunter Kaul, Dieter Kohn & Magali Cucchiarini

  2. Harvard University, Boston, USA

    David Zurakowski

  3. Department of Surgery, Institute for Experimental Surgery, Saarland University Medical Center, Homburg, Germany

    Michael D. Menger

Authors
  1. Henning Madry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Orth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gunter Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Zurakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael D. Menger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dieter Kohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Magali Cucchiarini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henning Madry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Madry, H., Orth, P., Kaul, G. 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 130, 1311–1322 (2010). https://doi.org/10.1007/s00402-010-1130-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00402-010-1130-3

Keywords

Search

Navigation