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Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo

Gene Therapy volume 21, pages 811–819 (2014)Cite this article

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Abstract

Direct therapeutic gene transfer is a promising tool to treat articular cartilage defects. Here, we tested the ability of an recombinant adeno-associated virus (rAAV) insulin-like growth factor I (IGF-I) vector to improve the early repair of cartilage lesions in vivo. The vector was administered for 3 weeks in osteochondral defects created in the knee joints of rabbits compared with control (lacZ) treatment and in cells that participate in the repair processes (mesenchymal stem cells, chondrocytes). Efficient IGF-I expression was observed in the treated lesions and in isolated cells in vitro. rAAV-mediated IGF-I overexpression was capable of stimulating the biologic activities (proliferation, matrix synthesis) both in vitro and in vivo. IGF-I treatment in vivo was well tolerated, revealing significant improvements of the repair capabilities of the entire osteochondral unit. IGF-I overexpression delayed terminal differentiation and hypertrophy in the newly formed cartilage, possibly due to contrasting effects upon the osteogenic expression of RUNX2 and β-catenin and to stimulating effects of this factor on the parathyroid hormone/parathyroid hormone-related protein pathway in this area. Production of IGF-I improved the reconstitution of the subchondral bone layer in the defects, showing increased RUNX2 expression levels in this zone. These findings show the potential of directly applying therapeutic rAAVs to treat cartilage lesions.

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Acknowledgements

We thank RJ Samulski (The Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USA), X Xiao (The Gene Therapy Center, University of Pittsburgh, Pittsburgh, PA, USA) and EF Terwilliger (Harvard Institutes of Medicine, Beth Israel Deaconess and Harvard Medical School, Boston, MA, USA) for providing genomic AAV-2 plasmid clones and the 293 cell line and AJ D’Ercole and B Moats-Staats (Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA) for the human IGF-IcDNA. We also thank G Schmitt (Center of Experimental Orthopaedics, Homburg/Saar, Germany) for technical assistance, D Zurakowski (Children's Hospital, Orthopaedic Surgery and Biostatistics, Harvard Medical School, Boston, MA, USA) for support in the statistical analyses and D Lajeunesse (Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Canada) and MD Menger (Institute for Experimental Surgery, Homburg/Saar, Germany) for helpful discussions. This work was supported by grants from the German Research Society (DFG) and the German Osteoarthritis Foundation (DAH).

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  1. Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg/Saar, Germany

    M Cucchiarini & H Madry

  2. Department of Orthopaedic Surgery, Saarland University Medical Center, Homburg/Saar, Germany

    H Madry

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  1. M Cucchiarini
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Correspondence to M Cucchiarini.

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Cucchiarini, M., Madry, H. Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo. Gene Ther 21, 811–819 (2014). https://doi.org/10.1038/gt.2014.58

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