Gadd45β Deficiency in Rheumatoid Arthritis Enhanced Synovitis Through JNK Signaling

Objective. JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45 beta, which is an NF-kappa B-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45 beta expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45 beta deficiency increases arthritis severity in passive K/BxN murine arthritis. Methods. Activation of the NF-kappa B and JNK pathways and Gadd45 beta expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45 beta(-/-) and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed. Results. Expression levels of the Gadd45 beta gene and protein were unexpectedly low in human RA synovium despite abundant NF-kappa B activity. Forced Gadd45 beta expression in human FLS attenuated tumor necrosis factor-induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45 beta deficiency exacerbated K/BxN serum-induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts. Conclusion. Deficient Gadd45 beta expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45 beta expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7.