IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion
Erik Lubberts, … , Pierre Miossec, Wim B. van den Berg
Erik Lubberts, … , Pierre Miossec, Wim B. van den Berg
Published June 15, 2000
Citation Information: J Clin Invest. 2000;105(12):1697-1710. https://doi.org/10.1172/JCI7739.
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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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Local IL-4 overexpression in the knee joint of collagen type II–immunize...
Local IL-4 overexpression in the knee joint of collagen type II–immunized mice suppresses local IL-6 and IL-12 protein levels. Collagen type II–immunized mice with a booster injection on day 22 were injected in the right and left knee joint on day 26 with 1.107 pfu of Ad5E1mIL-4 or Ad5del70-3 before onset of CIA was noted. Seven days after the intra-articular injection of the adenoviral vector, patella with adjacent synovium were isolated in a standardized manner from the knee joints and cultured for 1 hour in 200 μL RPMI 1640 with 0.1% BSA medium at room temperature. IL-6 and IL-12 levels were measured in these culture supernatants using a specific ELISA. Results are the mean ± SD of eight and nine patella washouts per group for IL-6 and IL-12, respectively. AP = 0.04 versus control group, by Mann-Whitney rank sum test.