Treatment with OPG and cellular gene therapy with IL-4 decrease bone resorption-associated inflammation in collagen-induced arthritis

Background

Interleukin-4 (IL-4) has anti-inflammatory effects in collagen-induced arthritis (CIA). Osteoprotegerin (OPG) inhibits bone resorption by binding the receptor activator of nuclear factor κB ligand (RANKL) and thereby inhibits binding of RANKL to RANK (receptor activator of nuclear factor κB) receptors of osteoclast precursors.

Objectives

To evaluate the action of OPG and IL-4 on the inflammatory process and the bone resorption associated with the inflammation.

Methods

CIA was induced in DBA/1 mice by immunization with bovine type II collagen (CII). Mice were treated by subcutaneous injections of OPG-Fc or with IL-4 DBA/1-transfected fibroblasts or both OPG-Fc+IL-4. Control groups received DBA/Tst or I1gG or saline. In one group CIA was not induced. Urinary deoxypyridinolin levels and total-body bone mineral density (BMD, Piximus Lunar) were measured at baseline and at sacrifice, allowing the measure of bone gain (BMD). Spleen cells were cultured after stimulation with CII, and cytokines were measured in the supernatants using ELISA techniques.

Results

CIA significantly improved in the IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4 and OPG+IL-4 groups versus nontreated CIA mice. Treatment with OPG significantly increased BMD in the total body. Moreover, the combination of IL-4 and OPG exerted an additive effect of BMD. D-pyridinolin levels decreased by 45% in OPG-treated mice and by 68% when mice were treated with both OPG and IL-4. INF-γ production was inhibited in IL-4 treated mice in comparison with controls. Interestingly, OPG also had a moderate effect on IFN-γ but potentiated the inhibitory effect observed in IL-4-treated mice.

Conclusion

OPG and IL-4 prevent bone loss in CIA in the mouse model and could have additive effects.