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 Trippel, Magali Cucchiarini

Research output: Contribution to journalArticle

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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 vitroand in explant cultures in situcompared 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.

Original languageEnglish
Pages (from-to)346-358
Number of pages13
JournalMolecular Medicine
Volume18
Issue number3
DOIs
StatePublished - Mar 2012

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Dependovirus
Cartilage
Intercellular Signaling Peptides and Proteins
Chondrocytes
Anabolic Agents
Insulin-Like Growth Factor Binding Protein 3
Mitogen-Activated Protein Kinase 3
Growth Factor Receptors
Mitogen-Activated Protein Kinase 1
Articular Cartilage
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Osteoarthritis
Signal Transduction
Down-Regulation
Survival

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

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. / Weimer, Anja; Madry, Henning; Venkatesan, Jagadeesh K.; Schmitt, Gertrud; Frisch, Janina; Wezel, Anna; Jung, Jochen; Kohn, Dieter; Terwilliger, Ernest F.; Trippel, Stephen; Cucchiarini, Magali.

In: Molecular Medicine, Vol. 18, No. 3, 03.2012, p. 346-358.

Research output: Contribution to journalArticle

Weimer, Anja ; Madry, Henning ; Venkatesan, Jagadeesh K. ; Schmitt, Gertrud ; Frisch, Janina ; Wezel, Anna ; Jung, Jochen ; Kohn, Dieter ; Terwilliger, Ernest F. ; Trippel, Stephen ; Cucchiarini, Magali. / 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. In: Molecular Medicine. 2012 ; Vol. 18, No. 3. pp. 346-358.
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