Skip to main content
SpringerLink
Log in

Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo

  • Experimental Study
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

The combination of chondrogenic factors might be necessary to adequately stimulate articular cartilage repair. In previous studies, enhanced repair was observed following transplantation of chondrocytes overexpressing human insulin-like growth factor I (IGF-I) or fibroblast growth factor 2 (FGF-2). Here, the hypothesis that co-overexpression of IGF-I and FGF-2 by transplanted articular chondrocytes enhances the early repair of cartilage defects in vivo and protects the neighbouring cartilage from degeneration was tested.

Methods

Lapine articular chondrocytes were transfected with expression plasmid vectors containing the cDNA for the Escherichia coli lacZ gene or co-transfected with the IGF-I and FGF-2 gene, encapsulated in alginate and transplanted into osteochondral defects in the knee joints of rabbits in vivo.

Results

After 3 weeks, co-overexpression of IGF-I/FGF-2 improved the macroscopic aspect of defects without affecting the synovial membrane. Immunoreactivity to type-I collagen, an indicator of fibrocartilage, was significantly lower in defects receiving IGF-I/FGF-2 implants. Importantly, combined IGF-I/FGF-2 overexpression significantly improved the histological repair score. Most remarkably, such enhanced cartilage repair was correlated with a 2.1-fold higher proteoglycan content of the repair tissue. Finally, there were less degenerative changes in the cartilage adjacent to the defects treated with IGF-I/FGF-2 implants.

Conclusion

The data demonstrate that combined gene delivery of therapeutic growth factors to cartilage defects may have value to promote cartilage repair. The results also suggest a protective effect of IGF-I/FGF-2 co-overexpression on the neighbouring articular cartilage. These findings support the concept of implementing gene transfer strategies for articular cartilage repair in a clinical setting.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 6

Similar content being viewed by others

References

  1. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Chia SL, Sawaji Y, Burleigh A, McLean C, Inglis J, Saklatvala J, Vincent T (2009) Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum 60:2019–2027

    Article  PubMed  CAS  Google Scholar 

  4. Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, Kohn D, Trippel SB, Terwilliger EF (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  PubMed  CAS  Google Scholar 

  5. Evans CH, Ghivizzani SC, Smith P, Shuler FD, Mi Z, Robbins PD (2000) Using gene therapy to protect and restore cartilage. Clin Orthop Relat Res 379(Suppl):S214–S219

    Article  PubMed  Google Scholar 

  6. Evans CH, Liu FJ, Glatt V, Hoyland JA, Kirker-Head C, Walsh A, Betz O, Wells JW, Betz V, Porter RM, Saad FA, Gerstenfeld LC, Einhorn TA, Harris MB, Vrahas MS (2009) Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur Cell Mater 18:96–111

    PubMed  CAS  Google Scholar 

  7. Farndale RW, Buttle DJ, Barrett AJ (1986) Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta 883:173–177

    PubMed  CAS  Google Scholar 

  8. 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  PubMed  CAS  Google Scholar 

  9. 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  PubMed  CAS  Google Scholar 

  10. Goldring MB, Goldring SR (2007) Osteoarthritis. J Cell Physiol 213:626–634

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ (2007) Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br 89:672–685

    PubMed  CAS  Google Scholar 

  13. Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ (2003) Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res 21:573–583

    Article  PubMed  CAS  Google Scholar 

  14. Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S, Loparic M, Haspl M, Windhager R, Pecina M (2010) Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther 17:779–789

    Article  PubMed  CAS  Google Scholar 

  15. Kaul G, Cucchiarini M, Arntzen D, Zurakowski D, Menger MD, Kohn D, Trippel SB, Madry H (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  PubMed  CAS  Google Scholar 

  16. Kiernan JA (1999) Histological and Histochemical Methods—Theory and Practice. Butterworth-Heinemann, Oxford

    Google Scholar 

  17. Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V, Ludvigsen TC, Roberts S, Solheim E, Strand T, Johansen O (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 

  18. 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  PubMed  CAS  Google Scholar 

  19. Madry H, Cucchiarini M, Stein U, Remberger K, Menger MD, Kohn D, Trippel SB (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  PubMed  CAS  Google Scholar 

  20. Madry H, Cucchiarini M, Terwilliger EF, Trippel SB (2003) Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther 14:393–402

    Article  PubMed  CAS  Google Scholar 

  21. Madry H, Emkey G, Zurakowski D, Trippel SB (2004) Overexpression of human fibroblast growth factor 2 stimulates cell proliferation in an ex vivo model of articular chondrocyte transplantation. J Gene Med 6:238–245

    Article  PubMed  CAS  Google Scholar 

  22. Madry H, Kaul G, Cucchiarini M, Stein U, Zurakowski D, Remberger K, Menger MD, Kohn D, Trippel SB (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  PubMed  CAS  Google Scholar 

  23. Madry H, Orth P, Kaul G, Zurakowski D, Menger MD, Kohn D, Cucchiarini M (2010) 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

    Article  PubMed  Google Scholar 

  24. Madry H, Zurakowski D, Trippel SB (2001) Overexpression of human insulin-like growth factor-I promotes new tissue formation in an ex vivo model of articular chondrocyte transplantation. Gene Ther 8:1443–1449

    Article  PubMed  CAS  Google Scholar 

  25. Martin JA, Brown T, Heiner A, Buckwalter JA (2004) Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology 41:479–491

    PubMed  CAS  Google Scholar 

  26. 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  PubMed  CAS  Google Scholar 

  27. O’Driscoll SW (1998) The healing and regeneration of articular cartilage. J Bone Joint Surg Am 80:1795–1812

    PubMed  Google Scholar 

  28. O’Driscoll SW, Keeley FW, Salter RB (1986) The chondrogenic potential of free autogenous periosteal grafts for biological resurfacing of major full-thickness defects in joint surfaces under the influence of continuous passive motion. An experimental investigation in the rabbit. J Bone Joint Surg Am 68:1017–1035

    PubMed  Google Scholar 

  29. 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  PubMed  CAS  Google Scholar 

  30. Rogachefsky RA, Dean DD, Howell DS, Altman RD (1993) Treatment of canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate. Osteoarthritis Cartilage 1:105–114

    Article  PubMed  CAS  Google Scholar 

  31. 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  PubMed  CAS  Google Scholar 

  32. 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

    PubMed  CAS  Google Scholar 

  33. Shida J, Jingushi S, Izumi T, Iwaki A, Sugioka Y (1996) Basic fibroblast growth factor stimulates articular cartilage enlargement in young rats in vivo. J Orthop Res 14:265–272

    Article  PubMed  CAS  Google Scholar 

  34. Solchaga LA, Yoo JU, Lundberg M, Dennis JE, Huibregtse BA, Goldberg VM, Caplan AI (2000) Hyaluronan-based polymers in the treatment of osteochondral defects. J Orthop Res 18:773–780

    Article  PubMed  CAS  Google Scholar 

  35. Tanaka H, Mizokami H, Shiigi E, Murata H, Ogasa H, Mine T, Kawai S (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  PubMed  CAS  Google Scholar 

  36. Trippel SB (1997) Growth factors as therapeutic agents. Instr Course Lect 46:473–476

    PubMed  CAS  Google Scholar 

  37. Vasiliadis HS, Danielson B, Ljungberg M, McKeon B, Lindahl A, Peterson L (2010) Autologous chondrocyte implantation in cartilage lesions of the knee: long-term evaluation with magnetic resonance imaging and delayed gadolinium-enhanced magnetic resonance imaging technique. Am J Sports Med 38:943–949

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by the Deutsche Forschungsgemeinschaft (DFG MA 2363/1-2 to H.M.). The authors thank E. Kabiljagic and E. Gluding for expert technical assistance.

Conflict of interest

The authors declare no competing financial interests. The authors, their immediate families and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

Author information

Authors and Affiliations

  1. Experimental Orthopaedics and Osteoarthritis Research, Saarland University, Kirrbergerstrasse, Building 37, 66421, Homburg, Germany

    Patrick Orth, Gunter Kaul, Magali Cucchiarini & Henning Madry

  2. Department of Orthopaedic Surgery, Saarland University Medical Center, Kirrbergerstrasse, Building 37, 66421, Homburg, Germany

    Patrick Orth, Dieter Kohn & Henning Madry

  3. Department of Biostatistics, Children’s Hospital, Harvard University, 300 Longwood Ave, Boston, MA, 02115, USA

    David Zurakowski

  4. Institute for Experimental Surgery, Saarland University Medical Center, Kirrbergerstrasse, Building 66, 66421, Homburg, Germany

    Michael D. Menger

Authors
  1. Patrick Orth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gunter Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Magali Cucchiarini
    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. Henning Madry
    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

Orth, P., Kaul, G., Cucchiarini, M. et al. Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo. Knee Surg Sports Traumatol Arthrosc 19, 2119–2130 (2011). https://doi.org/10.1007/s00167-011-1448-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00167-011-1448-6

Keywords

Search

Navigation