title: 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.
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 up-regulating 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.
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Weimer
authors.forename: Henning
authors.initials: H
authors.lastname: Madry
authors.forename: Jagadeesh K
authors.initials: JK
authors.lastname: Venkatesan
authors.forename: Gertrud
authors.initials: G
authors.lastname: Schmitt
authors.forename: Janina
authors.initials: J
authors.lastname: Frisch
authors.forename: Anna
authors.initials: A
authors.lastname: Wezel
authors.forename: Jochen
authors.initials: J
authors.lastname: Jung
authors.forename: Dieter
authors.initials: D
authors.lastname: Kohn
authors.forename: Ernest F
authors.initials: EF
authors.lastname: Terwilliger
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Trippel
authors.forename: Magali
authors.initials: M
authors.lastname: Cucchiarini
mesh_terms: D000368:Aged; D002356:Cartilage / Q000378:metabolism*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases