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
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.
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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