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

Bone destruction is the most difficult target in the treatment of rheumatoi d arthritis (RA). Here, we report that local overexpression of IL-4, introd uced 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 jo ints between Ad5E1mIL-4 and the control vector, but radiographic analysis r evealed impressive reduction of joint erosion and more compact bone structu re in the Ad5E1mIL-4 group. Although severe inflammation persisted in treat ed mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistan t 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 tis sue were suppressed, as were IL-6 and I L-12 protein production. Osteoprotegerin ligand (OPGL) expression was marke dly 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 patient s 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 implica tions for the prevention of hone erosion in arthritis.