Stimulation of proteoglycan synthesis by glucuronosyltransferase-1 gene delivery: a strategy to promote cartilage repair

N. Venkatesan, L. Barre, A. Benani, Patrick Netter, Jacques Magdalou, Sylvie Fournel-Gigleux, Mohamed Ouzzine

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    74 Citations (Scopus)

    Abstract

    Osteoarthritis is a degenerative joint disease characterized by a progressive loss of articular cartilage components, mainly proteoglycans (PGs), leading to destruction of the tissue. We investigate a therapeutic strategy based on stimulation of PG synthesis by gene transfer of the glycosaminoglycan (GAG)-synthesizing enzyme, ß1,3-glucuronosyltransferase-I (GlcAT-I) to promote cartilage repair. We previously reported that IL-1ß down-regulated the expression and activity of GlcAT-I in primary rat chondrocytes. Here, by using antisense oligonucleotides, we demonstrate that GlcAT-I inhibition impaired PG synthesis and deposition in articular cartilage explants, emphasizing the crucial role of this enzyme in PG anabolism. Thus, primary chondrocytes and cartilage explants were engineered by lipid-mediated gene delivery to efficiently overexpress a human GlcAT-I cDNA. Interestingly, GlcAT-I overexpression significantly enhanced GAG synthesis and deposition as evidenced by 35S-sulfate incorporation, histology, estimation of GAG content, and fluorophore-assisted carbohydrate electrophoresis analysis. Metabolic labeling and Western blot analyses further suggested that GlcAT-I expression led to an increase in the abundance rather than in the length of GAG chains. Importantly, GlcAT-I delivery was able to overcome IL-1ß-induced PG depletion and maintain the anabolic activity of chondrocytes. Moreover, GlcAT-I also restored PG synthesis to a normal level in cartilage explants previously depleted from endogenous PGs by IL-1ß-treatment. In concert, our investigations strongly indicated that GlcAT-I was able to control and reverse articular cartilage defects in terms of PG anabolism and GAG content associated with IL-1ß. This study provides a basis for a gene therapy approach to promote cartilage repair in degenerative joint diseases.
    Original languageEnglish
    Pages (from-to)18087-18092
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume101
    Issue number52
    DOIs
    Publication statusPublished - Dec 2004

    Keywords

    • Osteoarthritis
    • Gene transfer
    • Chondrocyte
    • Glycosyltransferase
    • Glycosaminoglycans

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