Open AccessGadd45β deficiency in rheumatoid arthritis: Enhanced synovitis through JNK signaling
Author(s) -
Svensson Camilla I.,
Inoue Tomoyuki,
Hammaker Deepa,
Fukushima Akihisa,
Papa Salvatore,
Franzoso Guido,
Schett Georg,
Corr Maripat,
Boyle David L.,
Firestein Gary S.
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24887
Subject(s) - arthritis , mmp3 , signal transduction , mmp9 , cancer research , electrophoretic mobility shift assay , inflammation , immunology , gadd45 , medicine , mmp1 , synovial membrane , nf κb , transcription factor , downregulation and upregulation , gene expression , chemistry , microbiology and biotechnology , biology , cell cycle , gene , cell cycle checkpoint , biochemistry , cancer
Objective JNK‐mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45β, which is an NF‐κB–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 Gadd45β expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45β deficiency increases arthritis severity in passive K/BxN murine arthritis. Methods Activation of the NF‐κB and JNK pathways and Gadd45β 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. Gadd45β −/− 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 Gadd45β gene and protein were unexpectedly low in human RA synovium despite abundant NF‐κB activity. Forced Gadd45β 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, Gadd45β 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 Gadd45β expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45β expression or by inhibiting the activity of JNK or its upstream regulator, MKK‐7.