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Molecular Medicine

, Volume 18, Issue 3, pp 346–358 | Cite as

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

  • Anja Weimer
  • Henning Madry
  • Jagadeesh K. Venkatesan
  • Gertrud Schmitt
  • Janina Frisch
  • Anna Wezel
  • Jochen Jung
  • Dieter Kohn
  • Ernest F Terwilliger
  • Stephen B. Trippel
  • Magali Cucchiarini
Research Article

Abstract

Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ, where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the expression of central effectors of the IGF-I axis by downregulating IGF-I inhibitors (IGF binding protein (IGFBP)-3 and IGFBP4) while upregulating key potentiators (IGFBP5, the IGF-I receptor and downstream mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK-1/2) and phosphatidylinisitol-3/Akt (PI3K/Akt) signal transduction pathways), probably explaining the enhanced responsiveness of OA cartilage to IGF-I treatment. These findings show the benefits of directly providing an IGF-I sequence to articular cartilage via rAAV for the future treatment of human osteoarthritis.

Notes

Acknowledgments

We thank RJ Samulski (The Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USA) and X Xiao (The Gene Therapy Center, University of Pittsburgh, Pittsburgh, PA, USA) for providing genomic AAV-2 plasmid clones and the 293 cell line. We also thank AJ D’Ercole and B Moats-Staats (Department of Pediatrics, University of North Carolina, Chapel Hill) for the human IGF-I cDNA.

This work was supported by grants from the German Research Society (Deutsche Forschungsgemeinschaft; grants DFG CU 55/1-1 and CU 55/1-2) and from the German Osteoarthritis Foundation (Deutsche Arthrose-Hilfe; grants DAH P65-A234-Kohn-EP3-cucc3-sonder-ko-38k-2004-07 and P66-A234-Kohn-EP4-cucc4-sonder-ko-30k-2006-08).

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Authors and Affiliations

  • Anja Weimer
    • 1
  • Henning Madry
    • 1
    • 2
  • Jagadeesh K. Venkatesan
    • 1
  • Gertrud Schmitt
    • 1
  • Janina Frisch
    • 1
  • Anna Wezel
    • 1
  • Jochen Jung
    • 2
  • Dieter Kohn
    • 2
  • Ernest F Terwilliger
    • 3
  • Stephen B. Trippel
    • 4
  • Magali Cucchiarini
    • 1
  1. 1.Center of Experimental OrthopaedicsSaarland University Medical CenterHomburg/SaarGermany
  2. 2.Department of Orthopaedic SurgerySaarland University Medical CenterHomburg/SaarGermany
  3. 3.Division of Experimental MedicineHarvard Institutes of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  4. 4.Department of Orthopaedic SurgeryIndiana University School of MedicineIndianapolisUSA

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