IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion
Erik Lubberts, Leo A.B. Joosten, Martine Chabaud, Liduine van den Bersselaar, Birgitte Oppers, Christina J.J. Coenen-de Roo, Carl D. Richards, Pierre Miossec, Wim B. van den Berg
Erik Lubberts, Leo A.B. Joosten, Martine Chabaud, Liduine van den Bersselaar, Birgitte Oppers, Christina J.J. Coenen-de Roo, Carl D. Richards, Pierre Miossec, Wim B. van den Berg
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Article

IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion

Abstract

Bone destruction is the most difficult target in the treatment of rheumatoid arthritis (RA). Here, we report that local overexpression of IL-4, introduced by a recombinant human type 5 adenovirus vector (Ad5E1mIL-4) prevents joint damage and bone erosion in the knees of mice with collagen arthritis (CIA). No difference was noted in the course of CIA in the injected knee joints between Ad5E1mIL-4 and the control vector, but radiographic analysis revealed impressive reduction of joint erosion and more compact bone structure in the Ad5E1mIL-4 group. Although severe inflammation persisted in treated mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistant acid phosphatase (TRAP) activity, indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production. Osteoprotegerin ligand (OPGL) expression was markedly suppressed by local IL-4, but no loss of OPG expression was noted with Ad5E1mIL-4 treatment. Finally, in in vitro studies, bone samples of patients with arthritis revealed consistent suppression by IL-4 of type I collagen breakdown. IL-4 also enhanced synthesis of type I procollagen, suggesting that it promoted tissue repair. These findings may have significant implications for the prevention of bone erosion in arthritis.

Authors

Erik Lubberts, Leo A.B. Joosten, Martine Chabaud, Liduine van den Bersselaar, Birgitte Oppers, Christina J.J. Coenen-de Roo, Carl D. Richards, Pierre Miossec, Wim B. van den Berg

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Adenoviral vector–mediated IL-4 expression in the mouse knee joint. (a) ...
Adenoviral vector–mediated IL-4 expression in the mouse knee joint. (a) 1.107 pfu of Ad5E1mIL-4 was given intra-articularly to naive C57bl/6 mice and patella with adjacent synovium was taken in a standardized manner on days 1, 2, 4, 7, and 14 to measure IL-4 in the washouts of joint tissue by ELISA. The control vector of the same dose and the washouts from the contralateral knee both gave rise to undetectable levels of IL-4 (not graphed). Results are expressed as mean ± SD of four mice per time point. (b) Various doses of AdE1mIL-4 were given intra-articularly to naive C57bl/6 mice, and IL-4 was measured in washouts of joint tissue at day 7 by ELISA. Results are expressed as mean ± SD of four mice per dose. The detection limit of the mIL-4 ELISA is 5 pg/mL.